EP1697347A1 - 5- or 6-substituted benzimidazole derivatives as inhibitors of respiratiory syncytial virus replication - Google Patents

5- or 6-substituted benzimidazole derivatives as inhibitors of respiratiory syncytial virus replication

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Publication number
EP1697347A1
EP1697347A1 EP04804954A EP04804954A EP1697347A1 EP 1697347 A1 EP1697347 A1 EP 1697347A1 EP 04804954 A EP04804954 A EP 04804954A EP 04804954 A EP04804954 A EP 04804954A EP 1697347 A1 EP1697347 A1 EP 1697347A1
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Prior art keywords
alkyl
substituted
het
formula
hydrogen
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EP04804954A
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German (de)
French (fr)
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EP1697347B1 (en
Inventor
Jean-François BONFANTI
Koenraad Jozef Lodewijk Andries
Jérôme Michel Claude FORTIN
Philippe Muller
Frédéric Marc Maurice DOUBLET
Christophe Meyer
Rudy Edmond Willebrords
Tom Valerius Josepha Gevers
Philip Maria Martha Bern Timmerman
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Janssen R&D Ireland ULC
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Tibotec Pharmaceuticals Ltd
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Priority to EP04804954A priority Critical patent/EP1697347B1/en
Priority to SI200431657T priority patent/SI1697347T1/en
Publication of EP1697347A1 publication Critical patent/EP1697347A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention is concerned with 5- or 6-substi ted-benzimidazole derivatives having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). It further concerns the preparation thereof and compositions comprising these compounds.
  • RSV respiratory syncytial virus
  • Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumovirinae together with bovine RSV virus.
  • Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSN infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
  • ribavirin a nucleoside analogue
  • the other two drugs, RespiGam ® and palivizumab, polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way.
  • the present invention concerns inhibitors of RSN replication, which can be represented by formula (1)
  • Q is Ar 2 , R 6a , pyrrolidinyl substituted with R 6 , piperidinyl substituted with R 6 or homopiperidinyl substituted with R 6 ;
  • G is a direct bond or Ci-ioalkanediyl optionally substituted with one or more substituents individually selected from the group consisting of hydroxy, Ci-ealkyloxy, Ar 1 C ⁇ -6 alkyloxy, Ci- ⁇ alkylthio, A ⁇ C ⁇ alkylthio, HO(-CH 2 -CH 2 -O) n -, C w alkyloxy(-CH 2 -CH 2 -0) deliberately- and Ar 1 C ⁇ alkyloxy(-CH 2 -CH 2 -O) wherever-;
  • R 1 is Ar 1 or a monocyclic or bicyclic heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydro- furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, quinolinyl, quinoxalinyl, benzofuranyl, benzotbienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthiridinyl, lH-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridiriyl, imidazo[l,2-a]- pyridin
  • R 4a and R 4 can be the same or can be different relative to one another, and are each independently hydrogen or C ⁇ aU yl; or
  • R 4a and R 4b taken together may form a bivalent radical of formula -(CH 2 ) S - wherein s is 4 or 5;
  • R 5 is hydrogen or
  • R 6 is hydrogen or C ⁇ alkyl optionally substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR ⁇ R 715 , C 3-7 cycloalkyl, Ar 2 , hydroxy, C 1- a!koxy, C ⁇ alkylthio, Ar ⁇ -oxy-, Ar ⁇ thio-, Ar 2 (CH2)nthio, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyl- carbonyl, Ar (CH 2 ) n carbonyl, aminocarbonyl- oxy, Ar 2 carbonyloxy, Ar 2 (CH 2 ) n Carbonyloxy, carbonyl(CH 2 ) n oxy, mono- or di(Ci alkyl)aminocarbonyl, mono- or di(C ⁇ -4alkyl)- aminocarbonyloxy, aminosulfonyl, mono- or (h(Ci.4alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyr
  • the invention also relates to the use of a compound of formula (I), or a prodrug,
  • N-oxide, addition salt, quaternary amitte, metal complex and stereochemically isomeric form thereof for the manufacture of a medicament for inhibiting RSN replication.
  • the invention relates to a method of inhibiting RSN replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (T), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof.
  • this invention relates to novel compounds of formula (I) as well as methods for preparing these compounds.
  • prodrug as used throughout this specification and claims means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • the reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8 th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15) describing prodrugs generally, is hereby incorporated.
  • Prodrugs are characterized by a good aqueous solubility and bioavailability, and are readily metabolized into the active inhibitors in vivo.
  • 'd-ioalkanediyl optionally substituted with one or more substituents' and 'Ci- ⁇ alkyl optionally substituted with one or more substituents' are meant to comprise d-ioalkanediyl or Ci- ⁇ al yl radicals having two or more substituents, for example two, three, four, five or six substituents, in particular two or three substituents, further in particular two substituents.
  • the upper limit of the number of substituents is determined by the number of hydrogen atoms that can be replaced as well as by the general properties of the substituents such as their bulkiness, these properties allowing the skilled person to determine said upper limit.
  • a group or part of a group is defined as mono- or polyhalo substituted C ⁇ _6alkyl, in particular Ci-ealkyl substituted with up to one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl.
  • perfluoro d-ealkyl groups which are Ci- ⁇ alkyl groups whereion all hydrogen atoms are replaced by fluoro atoms, e.g. pentafluoroethyl.
  • the halogen atoms may be the same or different.
  • Each of the monocyclic or bicyclic heterocycles in the definition of R 1 may optionally be substituted with 1 or where possible more substituents, such as 2, 3, 4 or 5, substituents.
  • said heterocycles may optionally be substituted with up to 4, up to 3, up to 2 substituents, or up to 1 substituent.
  • Each Ar 1 or Ar 2 may be unsubstituted phenyl or phenyl substituted with 1 or more substituents, such as 5 or 4 substituents or, which is preferred, up to 3 substituents, or up to two substituents, or with one substituent.
  • Ar 3 is phenyl, naphthalenyl, 1,2,3,4- tetrahydro-naphthalenyl or indanyl, which each may optionally with one or more substituents, such as 5 or 4 substituents or, which is preferred, up to 3 substituents, or up to two substituents, or with one substituent.
  • a hydroxyCi- ⁇ alkyl group when substituted on an oxygen atom or a nitrogen atom preferably is a hydroxyC 2 - 6 alkyl group wherein the hydroxy group and the oxygen or nitrogen are separated by at least two carbon atoms.
  • R 6 or R fe can be Ci- ⁇ alkyl substituted with one or more substituents selected from NR 7a R 7 , hydroxy, Ar 2 -oxy-, AXthio-, Ar 2 (CH 2 ) n oxy, Ar 2 (CH2)nthio, amino carbonyloxy, C 1- alkylcarbonyloxy, Ar 2 (CH2)nCarbonyloxy, C ⁇ alkoxycarbonyl(CH 2 )n ⁇ xy, mono- and ⁇ (C ⁇ .4alkyl)amino- carbonyloxy.
  • C ⁇ aUcyl preferably has at least two carbon atoms (i.e. C 2- 6alkyl) and the said substituents are not substituted on the carbon atom linked to the nitrogen bearing Q.
  • C 1-4 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1 -methylethyl, butyl and the like;
  • C 2 ⁇ alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyL 1 -methylethyl, butyl and the like;
  • Ci- ⁇ alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for and pentyl, hexyl, 2-methylbutyl and the like.
  • C2- 6 alkenyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having at least one double bond, and preferably having one double bond, and further having from 2 to 6 carbon atoms such as ethenyl, propenyl, buten- 1 -yl, buten-2-yL penten- 1 -yl, penten-2-yl, hexen- 1 -yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-l-yl and the like.
  • C3_7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C 2.5 alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like
  • C ⁇ alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like
  • C ⁇ alkanediyl is meant to include C ⁇ alkanediyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like
  • halo is generic to fluoro, chloro, bromo and iodo.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3 -pyridyl and 4-pyridyl
  • pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.
  • each definition is independent.
  • the term "compounds of formula (I)”, or “the present compounds” or similar term is meant to include the compounds of general formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms.
  • An interesting subgroup of the compounds of formula (I) or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms of the compounds of formula (I).
  • stereochemically isomeric forms as used hereinbefore defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.
  • the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantio- mers of the basic molecular structure of said compound All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure 1 concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl- tartaric acid, ditoluoyltartaric acid and camphosulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of formula (I) can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the absolute stereochemical configuration was not experimentally determined.
  • a person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
  • the present invention is also intended to include all isotopes of atoms occurring on the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohahc acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), maionic, succinic (i.e.
  • butane- dioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, j3-aminosalicylic, pamoic and the like acids.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or a ine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hytobamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifiuoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • any subgroup of compounds of formula (I) specified herein is meant to also comprise the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of this subgroup of compounds of formula (I).
  • One embodiment of the present invention concerns compounds of formula (T-a):
  • Another embodiment of the present invention concerns compounds of formula (I-b): wherein Q, R , G, R , R and R are as specified above in the definitions of the compounds of formula (I) or as in any of the subgroups of compounds specified herein.
  • Alk is d-ealkanediyl
  • R 8c has the same meanings of R 8a , and also maybe hydrogen;
  • R 9 , R 10 , R 11 independently from one another have the same meanings as the substituents on Ar 3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
  • Another particular embodiment of the present invention concerns compounds of formula (I-b-1):
  • Alk is Ci- ⁇ alkanediyl
  • R 8c has the same meanings of R 8a , and also may be hydrogen;
  • R 9 , R 10 , R 11 independently from one another have the same meanings as the substituents on Ar 3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
  • Another embodiment of the present invention concerns compounds of formula (I-c):
  • Another embodiment of the present invention concerns compounds of formula (I-d):
  • Another embodiment of the present invention concerns compounds of formula (I-e):
  • Still further embodiments comprise compounds of formula (I-c), (I-d) or (I-e) wherein t is 2, i.e. compounds of formulae
  • Another embodiment of the present invention concerns compounds of formula (I-d-2):
  • R 5 , R 6 , G andR 1 are as specified abpve or as in any of the subgroups of compounds specified herein; and t is 1, 2 or 3; preferably t is 2;
  • Alk is C 1-6 alkanediyl
  • R 8c has the same meanings of R 8a , and also may be hydrogen;
  • R 9 , R 10 , R 11 independently from one another have the same meanings as the substituents on Ar 3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
  • Another embodiment of the present invention concerns compounds of formula (I-e):
  • R 5 , R 6 , G, R 1 and R 3 are as specified above or as in any of the subgroups of compounds specified herein; and t is 1, 2 or 3; preferably t is 2;
  • R 8c has the same meanings of R 8a , and also may be hydrogen; R 9 , R 10 , R 11 independently from one another have the same meanings as the substituents on Ar 3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
  • Alk is ethylene or methylene, more preferably wherein Alk is methylene.
  • R 8c preferably is hydrogen, hydroxyd- ⁇ alkyl, aminocarbonyl-C 1-6 alkyl.
  • R 9 , R 10 , R 11 preferably and independently from one another are hydrogen, halo, hydroxy, mercapto, amino, cyano, Chalky!, d- ⁇ alkenyl, C ⁇ alkynyl, Ar 1 , hydroxyCi- ⁇ alkyl, CF 3 , aminod- ⁇ alkyl, cyanoC ⁇ -6alkyl, aminocarbonyl, d- ⁇ alkylthio, AXoxy, AXthio, AXamino, aminosulfonyl, aminocarbonyl-C ⁇ _ 6 alkyl, hydroxycarbonyl,
  • R 9 , R 10 , R 11 more preferably and independently from one another are hydrogen, halo, hydroxy, mercapto, cyano, d-ealkyl, C 2 ⁇ alkenyl, d- ⁇ alkynyl, Ar 1 , hydroxy- d- ⁇ alkyl, CF 3 , aminoC ⁇ - 6 alkyl, cyanoCi-ealkyl, aminocarbonyl, AXoxy, AXthio, Ar 1 -amino, aminosulfonyl, aminocarbonyl- hydroxycarbonyl-C 1-6 alkyl,
  • R 9 , R 10 , R 11 more preferably and independently from one another are halo, C 1-6 alkyl or hydroxyCi-ealkyl; or
  • R 9 , R 10 more preferably are as in (a), (b) or (c) and R 11 is hydrogen; or (e) R 9 , R 10 more preferably and independently from one another are C h alky! or hydroxy-d-ealkyl; and R 11 is hydrogen; or
  • R 9 , R 10 still more preferably are Ci- ⁇ alkyl and R 11 is hydrogen; or
  • R 9 is C 1-6 alkyl
  • R 10 is hydroxy-d- 6 alkyl
  • R 11 is hydrogen
  • Ci-ioalkanediyl more in particular wherein G is methylene.
  • R 1 is other than Ar 1 ;
  • R 1 is Ar 1 or a monocyclic heterocycle, which is as specified in the definitions of the compounds of formula (I) or any of the subgroups thereof.
  • R 1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy, and (C 1-6 alkyloxy)C ⁇ -6 alkyloxy; preferably wherein
  • R 1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy, or wherein
  • R 1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy and Ci- ⁇ alkyl; more preferably wherein (g) R 1 is pyridyl substituted with hydroxy and Ci-ealkyl; or more preferably wherein (h) R 1 is pyridyl substituted with hydroxy and methyl; or wherein (i) R 1 is 3-hydroxy-6-methylpyrid-2-yl.
  • R 1 is Ar 1 , quinolinyl, benzimidazolyl, a radical of formula pyrazinyl, or pyridyl; or wherein
  • R 1 is Ar 1 , quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl or pyridyl; wherein each of the radicals in (j) and (k) may optionally be substituted with the substitutents specified in the definition of the compounds of formula (I) and in particular pyridyl may be substituted as specified above in (a) to (i); or more specifically wherein
  • R 1 is Ar 1 , qumolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl or pyridyl, wherein each of these radicals may optionally be substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, or more specifically wherein (m) R 1 is Ar 1 , quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl or pyridyl, wherein each of these radicals may optionally be substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci- ⁇ alkyl, benzyloxy; or more specifically wherein (n) R 1 is phenyl optionally substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci- ⁇ alkyl, quinolinyl; a radical (c-4) wherein
  • Preferred subgroups of compounds of formula (I) or any of the subgroups of compounds of formula (I) are those wherein G is a direct bond or methylene and R 1 is as specified above in (a) - (s). Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein G is a direct bond and R 1 is a radical (c-4), in particular wherein m is 2, optionally substituted with up to two radicals selected from Ci- ⁇ alkyl. Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein or G is methylene and R 1 is as specified above in (a) — (s), but is other than a radical (c-4).
  • a particular embodiment of the present invention concerns compounds of formula (I) or of any of the subgroups of compounds of formula (I) specified herein wherein (a) one of R 2a and R 3a is selected from cyanoCi-ealkyl, cyanoC 2- 6alkenyl, Ar 3 C ⁇ -6alkyl, N(R 8a R 8b )C 1-6 alkyl, Ar 3 C 2 - 6 alkenyl, Ar 3 aminoC 1-6 alkyl, Het-aminoC 1 .
  • R 2a and R 3a is selected from cyanoCi-ealkyl, cyanod ⁇ alkenyl, Ar 3 C ⁇ -6alkyl, (Ar 3 )(OH)C ⁇ alkyl, Het-d-ealkyl, N(R 8a R 8b )C 1 - 6 alky ⁇ , Ar 3 C 2-6 alkenyl, Ar 3 aminoC 1- 6alkyl, Het-aminoCi- ⁇ alkyl, Het-Ci-ealkylanunoCi-ealkyl, Ar 3 thio- C ⁇ alkyl, Ar 3 aminocarbonyL Het-aminocarbonyl, Ar 3 (CH2) n aminocarbonyl, Het- (CH 2 ) n aminocarbonyl, Ar 3 carbonylamino, Ar 3 (CH 2 ) n amino; and the other one of R 2a andR 2b is hydrogen; or
  • R 2a and R 3a is selected from cyanoCi ⁇ alkyl, Ar 3 C ⁇ -ealkyl, Het-Ci- ⁇ alkyl, N(R 8a R 8b )C ⁇ .6alkyl, Ar 3 C 2-6 alkenyl, Het- C ⁇ - 6 alkylaminoC ⁇ alkyl, Ar 3 thiod ⁇ alkyl, Ar 3 aminocarbonyl, Het-aminocarbonyl, Ar 3 (CH 2 ) n aminocarbonyl, Het-(CH 2 ) n aminocarbonyl; and the other one of R 2a and R 2b is hydrogen; or
  • R a and R 3 is selected from cyanoCi-ealkyl, Ar 3 C 1- 6alkyl, Het-d ⁇ alkyl, Ar 3 aminocarbonyl; and the other one of R 28 and R 2 is hydrogen; or
  • R 2a and R 3a are selected from Ar 3 C 1-6 alkyl, N(R 8a R 8 )C ⁇ alkyl, Ar 3 C 2- 6alkenyl, Ar 3 aminoC ⁇ - 6 alkyl; and the other one of R 2 * 1 and R 2b is hydrogen; or (f) one of R 2a and R 3a is selected from N(R 8a R 8 )C 1-6 alkyl, Ar 3 aminoC 1-6 alkyl; and the other one of R 28 and R b is hydrogen; and for any of (a) - (f) in case R 2 is hydrogen then R 3 is hydrogen; in case R 2 is hydrogen then R 3 is hydrogen or or preferably then R 3 is hydrogen.
  • R 6 group is substituted on the nitrogen atom of the said pyrrolidinyl, piperidinyl or homopiperidinyl. More preferably the said pyrrolidinyl, piperidinyl or homopiperidinyl is linked to the -N(R 5 )- moiety via a 3-yl or in particular via a 4-yl link.
  • R 6a is substituted with two substituents or, preferably, with one substituent, each independently selected from the group consisting of trifluoromethyl, NR 7a R 7b , Ar 2 , hydroxy, C ⁇ alkoxy, Ar 2 (CH 2 )n ⁇ xy, hydroxycarbonyl, arninocarbonyl, C 1-4 alkoxycarbonyl, Ar 2 (CH2)nCarbony aminocarbonyloxy, C 1-4 alkylcarbonyloxy, Ar 2 carbonyloxy, mono- or aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and d-ealkyl; or in particular wherein
  • R 6a is C 1-6 alkyl substituted with one substituent and, optionally with a further substituent which is hydroxy, wherein said substituent is trifluoromethyl, NR ⁇ R , Ar 2 , hydroxy, Ar 2 (CH 2 ) n oxy, hydroxycarbonyl, aminocarbonyl, Ar 2 (CH2) carbonyl, aminocarbonyloxy, A ⁇ arbonyloxy, mono- or aminosulfonyl, mono- or di(Ci alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of
  • said heterocycle may optionally be substituted with with one or two radicals selected from oxo and C 1-6 alkyl; or further in particular
  • R 6a is Ci- ⁇ alkyl substituted with NR 7 R 7b , Ar 2 , hydroxy, C ⁇ alkoxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl C 1- alkoxycarbonyl, or C ⁇ alkyl substituted with two hydroxy radicals, or Ci- ⁇ alkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two C ⁇ aUcyl radicals; or further in particular (d) R 6a is C 1-6 alkyl substituted with NR ⁇ R , Ar 2 , hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or Ci- ⁇ alkyl substituted with two hydroxy radicals, or d- ⁇ alkyl substituted with a heterocycle selected from dioxolanyl,
  • R 6a is Chalky! substituted with Ar 2 or hydroxy, or d ⁇ alkyl substituted with two hydroxy radicals, or substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, wherem each of said heterocycle may optionally be substituted with one or two C ⁇ aUcyl radicals; or preferably (f) R 6a is d- ⁇ alkyl substituted with Ar 2 or hydroxy, or Ci- ⁇ alkyl substituted with two hydroxy radicals, or C h al y!
  • R 6a is substituted with two hydroxy radicals, or substituted with piperidinyl or with piperazinyl; or more preferably
  • R 6a is d ⁇ alkyl substituted with Ar 2 or d ⁇ alkyl substituted with piperidinyl or with piperazinyl.
  • the radicals pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl are linked by their nitrogen atom to the Ci- ⁇ alkyl on which they are substituted.
  • R 6 is hydrogen or optionally substituted with two substituents or, preferably, with one substituent, each independently selected from the group consisting of trifluoromethyl, Ar 2 (CH2) n oxy, hydroxycarbonyl, aminocarbonyl, C 1- alkylcarbonyl, Ar 2 (CH 2 ) n Carbonyl, aminocarbonyloxy, mono- or di(C 1- alkyl)aminocarbonyl, aminosulfonyl, mono- or di(d- alky ⁇ )- aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and or in particular
  • R 6 is hydrogen or C ⁇ aUcyl optionally substituted with one substituent and, optionally with a further substituent which is hydroxy, wherein said substituent is trifluoromethyl, hydroxycarbonyl, aminocarbonyl, C 1- alkylcarbonyl, Ar 2 (CH 2 ) n - carbonyl, aminocarbonyloxy, mono- or di(C 1- alkyl)aminocarbonyl, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and or further in particular
  • R 6 is hydrogen or Ar 2 , hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl, or Ci-ealkyl substituted with two hydroxy radicals, or Ci-ealkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two d- ⁇ alkyl radicals; or further in particular (d) R 6 is hydrogen or d-ealkyl optionally substituted with NR 7a R 7b , Ar 2 , hydroxy, hydroxycarbonyl, aminocarbonyl, arninosulfonyl or d ⁇ alkyl substituted with two hydroxy radicals, or C ⁇ aU yl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl,
  • R 6 is hydrogen or C ⁇ - 6 alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl or aminosulfonyl, or Ci- ⁇ alkyl substituted with two hydroxy radicals, or Ci- ⁇ alkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with one or two Ci- ⁇ alkyl radicals; or preferably
  • R 6 is hydrogen or d- ⁇ alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl, aminosulfonyl, or d- ⁇ alkyl substituted with two hydroxy radicals, or d- ⁇ alkyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkyl- piperazinyl; or preferably
  • R 6 is hydrogen or d ⁇ alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl or aminosulfonyl; or preferably
  • R 6 is hydrogen or d-ealkyl substituted with Ar 2 or Chalky! substituted with piperidinyl or with piperazinyl; or
  • R 6 is Ci-ealkyl
  • radicals pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl are linked by their nitrogen atom to the d- ⁇ alkyl on which they are substituted.
  • R 8a is Ar 3 , Chalky!, hydroxyd ⁇ alkyl, Ci ⁇ alkoxyC ⁇ alkyl, cyanoC ⁇ - 6 alkyl, aminod-ealkyl, mono-or Ar 3 C ⁇ -6alkyl, Het-Ci- ⁇ alkyl, aminocarbonyl-C ⁇ -6-alkyl, carboxyl-d-e-alkyl; and R 81 ' is Ar 3 ; or
  • R 8a is Ar 3 , C h alky!, Het-Ci- ⁇ alkyl, amino- carbonyl-d-6-alkyl; and R 8b is Ar 3 ; or
  • R is hydroxyd-ealkyl, aminocarbonyl-d- 6 -alkyl; and R > 8b : is A k_r3 ;. or
  • R 8a is Ar 3 and R 8b is Ar 3 ; or (e) R 8a is d ⁇ alkyl, hydroxyd-ealkyl, Ar 3 C 1- galkyl, Het-C 1-6 alkyl, aminocarbonyl-
  • Ar 1 is phenyl or phenyl substituted with 1, 2, 3 substituents or with 1, 2 substituents selected from those mentioned in the definition of the compounds of formula (I) or of any subgroup thereof.
  • Ar 1 preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo, hydroxy, C ⁇ - 6 alkyl, hydroxyCi_ 6 alkyl, trifluormethyl, and Ci- ⁇ alkyloxy;
  • Ar 2 is phenyl or phenyl substituted with 1, 2, 3 substituents or with 1, 2 substituents selected from the group consisting of those mentioned in the definition of the compounds of formula (I) or of any subgroup thereof.
  • subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Ar 3 is phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl, or preferably wherein Ar 3 is phenyl, naphthalenyl or indanyl; wherein said phenyl may optionally and each individually be substituted with one or more, such as 2, 3 or 4, substituents selected from the group consisting of substituents of Ar 3 in the definitions of the compounds (I).
  • Ar 3 is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, mercapto, amino, cyano, Ci-ealkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ar 1 , hydroxyd ⁇ alkyl, CF 3 , aminoC ⁇ alkyl, cyanoCi- ⁇ alkyl, aminocarbonyl, Ci- ⁇ alkyloxy, d-ealkylthio, AXoxy, AXthio, Ar 1 -amino, aminosulfonyl, aminocarbonyl-d-ealkyl, hydroxycarbonyl-d- ⁇ alkyl, hydroxycarbonyl, or C alkoxycarbonyl; or wherein
  • Ar 3 is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, mercapto, cyano, C h alky!, C 2-6 alkenyl, C 2-6 alkynyl, Ar 1 , hydroxyd- ⁇ alkyl, CF 3 , aminoCi-ealkyl, cyanoC 1-6 alkyl, aminocarbonyl, C ⁇ - 6 alkylthio, Ar 1 -oxy, AXthio, AXamino, aminosulfonyl, aminocarbonyl-Ci-ealkyl, hydroxycarbonyl-Ci- ⁇ alkyl, or wherein
  • Ar 3 is phenyl optionally substituted with one, two or three substituents selected from halo, Ci ⁇ alkyl or hydroxyd-ealkyl; or
  • Ar 3 is phenyl substituted with one, two or three substituents selected from halo, Ci-ealkyl or hydroxyC 1-6 alkyl; or
  • Ar 3 is phenyl optionally substituted with one, two or three substituents selected from halo, or hydroxyCi-ealkyl; or (f) Ar 3 is phenyl substituted with one, two or three substituents selected from halo, d- ⁇ alkyl or hydroxyd- ⁇ alkyl; or (g) Ar 3 is phenyl substituted with one or two substituents selected from halo, or hydroxyCi-ealkyl; or (h) Ar 3 is phenyl optionally substituted with one or two substituents selected from Cnjalkyl or hydroxyC ⁇ -6alkyl.
  • Ar 3 is as defined for Ar 2 , more in particular Ar 3 is as defined for Ar 1 .
  • Het is furanyl, imidazolyl, moipholinyl, benzodioxolyl, quinolinyl, indolinyl, which may optionally be substituted with hydroxyC ⁇ -6alkyl or with one or two d ⁇ alkyl radicals; or
  • Het is morpholinyl, which may optionally be substituted with one or two radicals; or
  • Preferred compounds are those compounds listed in tables 1 through 5, more in particular the compound numbers 1 to 77, 138, 143 to 165 and 171 to 177.
  • R 1 , R 2 " , R 2b , R 3a , R 3b R 5 have the meanings defined above for the compounds of formula (I) or of any of the subgroups thereof.
  • W is an appropriate leaving group, preferably it is chloro or bromo.
  • the reaction of this scheme is typically conducted in a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHC1 3 , toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like.
  • a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHC1 3 , toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like.
  • t, R 1 , R 2a , R 2 , R 3 , R 5 have the meanings defined above for the compounds of formula (I) or of any of the subgroups thereof.
  • W is an appropriate leaving group, preferably it is chloro or bromo.
  • the reaction of this scheme can be conducted in a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHC1 3 , toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like.
  • a base may be added to pick up the acid that is liberated during the reaction.
  • certain catalysts such as iodide salts (e.g.
  • This reductive alkylation is done in a suitable solvent, e.g. an alcohol, using hydrogen in the presence of a metal catalyst such as Pd or NaBH 3 CN.
  • Some of the compounds of formula (I) can also be prepared starting from precursors of the compounds of formula (I) using appropriate functional group transformation reactions.
  • Precursors of the compounds of formula (I) for example are those wherein R 2a or R 2 is Ci- alkoxycarbonyl or substituted with which can be reduced, e.g. with LiAlHU, to the corresponding compounds of formula (I) wherein R 2a or R 2b is The latter group can be oxidized with a mild oxidant to an aldehyde group, e.g. with MnO 2 , which can further be derivatized with amines, e.g. with a reductive amination process, to the corresponding mono(derivatizedC 1-6 aIkyl)- amines.
  • R 23 or R 2b has formula -Alk-NR 8a R 8b .
  • precursors of the compounds of formula (T) wherein R 28 or R 2 is hydroxyd ⁇ alkyl can be converted to the corresponding haloCi- ⁇ alkyl compounds, e.g. by treatment with a suitable halogenating agent such as SOCl 2 , which compounds subsequently are reacted with an amine or amine derivative.
  • a suitable halogenating agent such as SOCl 2
  • This reaction sequence may be done starting from (Vll-a) or (VTI-b) separately but also can be done using a mixture of (VTI-a) and (VTI-b) and subsequently separating the reaction products either at the end of the reaction sequence or in an intermediate step.
  • (l-g-2) Precursors of the compounds of formula (I) wherein R 2a or R 2b is an aldehyde can be converted to the corresponding compounds wherein R 2a or R 2b is substituted C ⁇ alkenyl (I-g-1) or (I-g-2), by a Wittig reaction or a Wittig-Horner reaction.
  • a Wittig type reagent such as a triphenylphosphoniumyUde in a suitable reaction-inert solvent such as an ether, starting from triphenylphosphine and a halo derivative.
  • the Wittig-Horner reaction is performed using a phosphonate, such as e.g.
  • a reagent of formula ⁇ (C ⁇ -6 alkyloxy)-P( O)-CH 2 -CH -CN in the presence of a base, preferably a strong base, in an aprotic organic solvent.
  • a base preferably a strong base
  • Compounds wherein R 2a or R 3a is substituted Qz-salkenyl can be reduced to the corresponding compounds wherein R 2a or R 3a is substituted C 2- 6alkyl (I-i-1) or (I-i-2), e.g. with hydrogen in the presence of a noble metal catalyst such as Pd/C.
  • the cyano group in turn can be reduced to the corresponding melhyleneamine (-CH2-NH2) group with hydrogen in the presence of a catalyst such as Raney Ni, in a suitable solvent such as methanol/ammonia.
  • This reaction yields compounds (I-j-1) and (I-j-2) which can be mono-alkylated or double alkylated to yield compounds (I-k-1), (I-k-2) and (1-1-1), (1-1-2).
  • These alkylations may be done by a reductive alkylation reaction using an aldehyde or ketone in the presence of hydrogen and a catalyst (yielding mono-alkyl derivatives) or with suitably substituted alkyl halides (yielding mono- or dialkyl derivatives).
  • R 28"1 represents CN, Ar 3 or Het
  • Alk 1 represents C -6 alkanediyl radicals (which are as Ci-ealkanediyl, but having from 4 — 6 carbon atoms)
  • R and R , 8b have the same meanings as defined in this specificationa and claims, but preferably are other than Ar 3 .
  • R 6b is Ci-ealkyl optionally substituted with two substituents or, preferably, with one substituent, each independently selected from the group consisting of trifluoromethyl, Ar 2 , hydroxy, Ci ⁇ alkoxy, Ar 2 (CH2) n oxy, hydroxycarbonyl, aminocarbonyl, C 1- alkylcarbonyl, C 1- alkoxycarbonyl, Ar 2 (CH2) n carbonyl, aminocarbonyloxy, Ar bonyloxy, mono- or (C 1-4 alkyl)amino- carbonyl, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and Ci- ⁇ alkyl; or in
  • R 611 is Ci-ealkyl optionally substituted with one substituent and, optionally with a further substituent which is hydroxy, wherein said substituent is trifluoromethyl, Ar 2 , hydroxy, C ⁇ -4alkoxy, Ar 2 (CH 2 ) n oxy, hydroxycarbonyl, aminocarbonyl, C 1-4 alkylcarbonyl, C ⁇ -4 alkoxycarbonyl, Ar 2 (CH 2 ) n carbonyl, aminocarbonyloxy, C 1- alkylcarbonyloxy, Ar 2 carbonyloxy, mono- or di(C ⁇ all ⁇ l)aminocarbonyl, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two
  • R 615 is C 1-6 alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl or arninosulfonyl, or substituted with two hydroxy radicals, or Ci- ⁇ alkyl substituted with a heterocycle selected from dioxolanyl, pyrroUdinyl, piperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with one or two C ⁇ _ 6 alkyl radicals; or preferably
  • R ⁇ is Ci- 6 alkyl optionally substituted with Ar 2 , hydroxy, aminocarbonyl, aminosulfonyl, or substituted with two hydroxy radicals, or dialkyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-C ⁇ alkyl-piperazinyl; or preferably (g) R 61 ' is C h alky! optionally substituted with Ar 2 , hydroxy, aminocarbonyl or aminosulfonyl; or preferably (h) R ⁇ is Cwalkyl.
  • the radicals pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl are linked by their nitrogen atom to the dialkyl on which they are substituted Moreover these compounds have found to possess antiviral properties, in particular to possess RSV inhibitory activity.
  • these compounds have found to possess antiviral properties, in particular to possess RSV inhibitory activity.
  • the terms 'pharmaceutically acceptable salt forms' and the 'stereoisomeric forms' have the meanings specified above in this specification.
  • G, R 1 , R 28 , R 2b , R 3 , R 5 , R 8a and R 815 are as specified in any of the subgroups mentioned in this specification and claims.
  • Preferred are those novel compounds mentioned in the previous paragraphs wherein G is d ⁇ alkanediyl, more preferably wherein G is methylene; and/or wherein R 24 , R 2b , R 3 , R 5 are all hydrogen; and/or R 1 is pyridyl being substituted as outlined in this specification and claims, in particular R 1 is pyridyl being substituted with one or two substituents selected from C ⁇ -6alkyl and hydroxy.
  • ⁇ itro groups can be reduced to amino groups, which subsequently may be alkylated to mono- or dialkyla ino groups, or acylated to aiylcarbonylamino or alkylcarbonyl- amino and the like groups. Cyano groups may be reduced to aminomethylene groups, which similarly may be derivatized.
  • a diaminobenzene (VI) is cyclized with urea in a suitable solvent, e.g. xylene, to yield a benzimidazolone (VII).
  • a suitable solvent e.g. xylene
  • the latter is converted to a benzimidazole derivative (VHI) wherein is a leaving group as specified above, in particular by reaction of (VII) with a suitable halogenating agent, for example POCl 3 , and the resulting intermediate (VlJJL) is reacted with the amine derivative (IX) to obtain intermediate (II).
  • the intermediates of formula (TV) can be prepared by reacting intermediates (IX) with an amine (X) wherein Q is a a pyrrolinyl, piperdinyl or homopiperidinyl group wherein the nitrogen is substituted with a protective group to yield precursors of (TV) which ca be converted to intermediates (TV) by removing the protective group.
  • Suitable protecting groups for this purpose comprise alkyloxycarbonyl groups such as methoxy or efhoxycarbonyl, which can be removed with a base, or benzyl or benzyloxycarbonyl groups, which can be removed with hydrogen in the presence of a catalyst.
  • the compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form.
  • Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with, an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper- oxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • 3-chlorobenzenecarbo- peroxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tbutyl hydro-peroxide.
  • Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and rnixtures of such solvents.
  • Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter- current distribution, liquid chromatography and the like.
  • the compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I), which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional ci stallization and the enantiomers are liberated therefrom by alkali or acid.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospeciflcally.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount in this context is an amount sufficient to prophylaxictically act against, to stabilize or to reduce viral infection, and in particular RSV viral infection, in infected subjects or subjects being at risk of being infected.
  • this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I) as specified herein.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • the compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
  • the present invention also provides a pharmaceutical composition adapted for adrninistration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition adapted for adrninistration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the compounds of formula (T) show antiviral properties.
  • Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV).
  • RSV human and bovine respiratory syncytial virus
  • a number of the compounds of this invention moreover are active against mutated strains of RSV.
  • many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
  • the in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay.
  • the in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31-42).
  • the compounds of formula (I) or any subgroup thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms are useful in the treatment of individuals experiencing a viral infection, particularly a RSV infection, and for the prophylaxis of these infectionLS.
  • the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular the respiratory syncytial virus.
  • the compounds of the present invention or any subgroup thereof may therefore be used as medicines.
  • Said use as a medicine or method of treatment comprises the systemic adrninistration to viral infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the RSV infection.
  • the present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly RSV infection.
  • the present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by RSV, said method comprising the administration of an anti-virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I), as specified herein.
  • an antiviral effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
  • the combination of another antiviral agent and a compound of formula (I) can be used as a medicine.
  • the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment.
  • the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections. Examples
  • LCT electrospray ionisation in positive mode, scanning mode from 100 to 900 amu; Xterra MS C18 (Waters, Milford, MA) 5 ⁇ , 3.9 x 150 mm); flow rate 1 rrJ/min.
  • Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient from 100 % A for 3 min to 100% B in 5 min., 100% B for 6 rnin to 100 % A in 3 min, and equilibrate again with 100 % A for 3 min).
  • ZQ electrospray ionisation in both positive and negative (pulsed) mode scanning from 100 to 1000 amu; Xterra RP C18 (Waters, Milford, MA) 5 ⁇ m, 3.9 x 150 mm); flow rate 1 ml/ in.
  • Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient condition from 10O % A for 3 min to 100% B in 5 min., 100% B for 6 min to 100 % A in 3 min, and equilibrate again with 100 % A for 3 min).
  • Variant 1 A mixture of b-2 (0.0001 mol), 3,5-dichloro aniline (0.0001 mol), BH 3 CN on solid support (0.0001 mol) and CH 3 CO 2 H (2 drops) in CH 3 OH (4ml) was stirred at room temperature for 24 hours. The solution was filtered. The filtrate was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: 87/12/1.5; 5 ⁇ m).
  • Variant 2 b-2 (0.0005 mol), NaBH 3 CN (0.0006 mol), and then CH 3 CO2H (0.2ml) were added at room temperature to a rnixture of 3 -methyl-aniline (0.0006 mol) in CH 3 CN (20ml). The mixture was stirred at room temperature for 12 hours. H2O was added. The mixture was saturated with K2CO 3 (powder) and extracted with CH 2 Cl 2 /CH 3 OH. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness.
  • R is defined as Ar 3 , Het 1 , Het 1 (CH 2 ) n or Het 1 (CH 2 ) n .
  • Intermediate d-2 (melting point: 262°C) was prepared analogous to the procedure described for intermediate a-11.
  • Intermediate d-3 was prepared analogous to the procedure described for intermediate a-12.
  • e-5 (0.0088 mol) was added portion wise to a 48% solution of HBr in water (40r ⁇ l).
  • LiAlH 4 (0.0008 mol) was added to a mixture of h-4 (0.0004 mol) in tetiahydrofuran (20ml) at 5°C under N 2 flow. The mixture was stirred at 5°C for 1 hour, then brought to room temperature and stirred for 4 hours. A minimum of H 2 O and then CH 2 C1 were added The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue (0.22g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 85/15/1; 15-40um). The pure fractions were collected and the solvent was evaporated.
  • Intermediate i-3 was prepared in an analogous way to the procedure described for intermediate a-2.
  • Intermediate i-4 was prepared in an analogous way to the procedure described for intermediate a-3.
  • Intermediate i-5 was prepared in an analogous way to the procedure described for intermediate a-5.
  • Intermediate i-8 was prepared in an analogous way to the procedure described for intermediate a-9.
  • Intermediate i-9 was prepared in an analogous way to the procedure described for intermediate a-11.
  • Intermediate i-10 (melting point: 221°C) was prepared in an analogous way to the procedure described for intermediate h-2.
  • Intermediate i-11 was prepared in an analogous way to the procedure described for intermediate h-3.
  • Intermediate j-5 was prepared in an analogous way to the procedure described for intermediate h-2.
  • Intermediate j-6 (melting point: 207°C) was prepared in an analogous way to the procedure described for intermediate i-13.
  • CH 3 CO 2 H (0.2ml) was added at room temperature to a mixture of k-3 (0.0004 mol), 3,5-dimethyl-aniline (0.0005 mol) and NaBH 3 CN (0.0005 mol) in CH 3 CN (20ml). The mixture was stirred at room temperature for 30 minutes. CH 3 CO2H (0.2ml) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH 2 CI 2 . The organic layer was washed with a 10% solution of K 2 CO 3 in water, dried (over MgSO ), filtered and the solvent was evaporated until dryness.
  • Intermediate 1-2 (melting point: 210°C) was prepared in an analogous way to the procedure described for intermediate k-2.
  • Intermediate 1-3 was prepared in an analogous way to the procedure described for intermediate k-3.
  • Intermediate 1-4 was prepared in an analogous way to the procedure described for compound k-4.
  • n-2 (0.0066 mol), n-3 (0.0073 mol) and K 2 CO 3 (0.02 mol) in dimethylformamide (25ml) was stirred at room temperature for 24 hours, poured into H 2 O and extracted with CH 2 C1 2 . The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue was taken up in ⁇ m 3 CN/diisopropylether. The precipitate was filtered, washed with H 2 O and dried, yielding 1.8g of the mixture of intermediates n-4 and n-5 (61%).
  • CH 3 CO 2 H (0.3ml) was added to a inixture of n-8 (0.0006 mol), 3,5-dimethyl-aniline (0.0007 mol) andNaBH 3 CN (0.0007 mol) in CH 3 CN (30ml). The mixture was stirred at room temperature for 30 minutes. CH3CO2H (0.3ml) was added. The mixture was stirred at room temperature for 24 hours. The solvent was evaporated until dryness. The residue was taken up in 2-propanone/HCl 5N/ethanol. The mixture was stirred at 80°C for 12 hours. The solvent was evaporated until dryness. The mixture was extracted with CH2CI2. The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness.
  • the residue (0.39g) was purified by column chromatography over silica gel (eluent: CH 2 CyGH 3 OH/NH 4 OH 90/10/0.5; lO ⁇ m). The pure fractions were collected and the solvent was evaporated. The residue (0.119g, 59%) was taken up in CHsCN/diisopropylether.
  • Example 18 In vitro screening for activity against Respiratory Syncytial Virus.
  • the percent protection against cytopathology caused by viruses (antiviral activity or EC 5 o) achieved by tested compounds and their cytotoxicity (CC 50 ) are both calculated from dose-response curves.
  • the selectivity of the antiviral effect is represented by the selectivity index (SI), calculated by dividing the CC 50 (cytotoxic dose for 50% of the cells) by the EC50 (antiviral activity for 50 % of the cells).
  • SI selectivity index
  • the tables in the above experimental part list the category to which each of the prepared compounds belong : Compounds belonging to activity category "A” have an pEC 5 o (-log of EC 5 0 when expressed in molar units) equal to or more than 7.
  • Compounds belonging to activity category "B” have a pEC50 value between 6 and 7.
  • Compounds belonging to activity category "C” have a pEC50 value equal to or below 6.
  • TCID 50 of Respiratory Syncytial Virus was added to two of the three rows in a volume of 50 ⁇ l.
  • the same volume of medium was added to the third row to measure the cytotoxicity of the compounds at the same concentrations as those used to measure the antiviral activity.
  • a suspension (4 x 10 5 cells/ml) of HeLa cells was added to all wells in a volume of 50 ⁇ l.
  • the cultures were incubated at 37°C in a 5% CO 2 atmosphere. Seven, days after infection the cytotoxicity and the antiviral activity was examined spectrophotometrically.

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Abstract

The present invention concerns 5- or 6-substituted-benzimidazole derivatives having inhibitory activity on the replication of the respiratory syncytial virus and having the formula (I) a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein Q is Ar2, R6, pyrrolidinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6, G is a direct bond or optionally substituted C1-10alkanediyl; R1 is Arl or a monocyclic or bicyclic heterocycle; one of R 2a and R2b is cyanoCl-6alkyl, cyanoC2-6alkenyl, Ar3Cl-6alkyl, Het­-C1-6alky1, N(R8aR8b)Cl-6alkyl, Ar3C2-6alkenyl, Het-C2-6alkenyl, Ar3 aminoCl-6alkyl, Het­aminoCl-6alkyl, Ar3thioC1-6 alkyl, Het-thioC1-6alkyl, Ar3sulfonylC1-6 alkyl, Het­sulfonylC1-6alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl, Ar3carbonylamino, Het-carbonylamino, Ar3(CH2)ncarbonylamino, Het-(CH2)ncarbonylamino, and the other one of R2a and R2b is hydrogen; in case R2a is hydrogen, then R3 is hydrogen; in case R2b is hydrogen, the R3 is hydrogen or C1-6alkyl. It further concerns their preparation and compositions comprising them, as well as their use as a medicine.

Description

5- OR 6-SUBSTΪTUTED BENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF RESPIRATORY SYNCYTIAL VIRUS REPLICATION
The present invention is concerned with 5- or 6-substi ted-benzimidazole derivatives having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). It further concerns the preparation thereof and compositions comprising these compounds.
Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumovirinae together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSN infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A " andB.
Today only three drugs have been approved for use against RSN infection. A first one is ribavirin, a nucleoside analogue, provides an aerosol treatment for serious RSN infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. The other two drugs, RespiGam® and palivizumab, polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way.
Other attempts to develop a safe and effective RSN vaccine have all met with failure thus far. Inactivated vaccines failed to protect against disease, and in fact in some cases enhanced disease during subsequent infection. Life attenuated vaccines have been tried with limited success. Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSN replication. Previously, benzimidazoles and imidazopyridines as inhibitors of RSN replication have been described in WO 01/00611, WO 01/00612 and WO 01/00615.
Several series of benzimidazolyl and imidazopyridinyl piperidines have been described in patents, patent applications and publications of janssen Pharmaceutica Ν.N. as compounds possessing antMstaminic properties. See for example EP-A-5 318, EP-A-99 139, EP-A-145 037, WO-92/01687, Janssens F. et al. in Journal of Medicinal Chemistry, Am. Chem. Soc, Nol. 28, no. 12, pp. 1934-1943 (1985).
The present invention concerns inhibitors of RSN replication, which can be represented by formula (1)
their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein
Q is Ar2, R6a, pyrrolidinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6;
G is a direct bond or Ci-ioalkanediyl optionally substituted with one or more substituents individually selected from the group consisting of hydroxy, Ci-ealkyloxy, Ar1Cι-6alkyloxy, Ci-βalkylthio, A^C^alkylthio, HO(-CH2-CH2-O)n-, Cwalkyloxy(-CH2-CH2-0)„- and Ar1Cι^alkyloxy(-CH2-CH2-O)„-;
R1 is Ar1 or a monocyclic or bicyclic heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydro- furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, quinolinyl, quinoxalinyl, benzofuranyl, benzotbienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthiridinyl, lH-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridiriyl, imidazo[l,2-a]- pyridinyl, 2,3-dihydro-l,4-dioxino[2,3-b]pyridyl or a radical of formula
wherein each of said monocyclic or bicyclic heterocycles may optionally be substituted with 1 or where possible more, such as 2, 3, 4 or 5, substituents individually selected from the group of substituents consisting of halo, hydroxy, amino, cyano, carboxyl, Chalky!, Cι-6alkyloxy, Ci-ealkyloxyCi-eal yl, Ar1, mono-or di(Cι-6alkyl)aminoCι-^alkyl, polyhaloCi-δalkyl, Ci-salkylcarbonylamino, Cι-6alkyl-SO2-NR4a-, AXSO^NR48-, C1-6alkyloxycarbonyl, -C(=O)-NR4aR4 , HO(-CH2-CH2-O)„-, halo(-CH2-CH2-0)n-, Ar1C1-6alkyloxy(-CH2-CH2-O)n- and mono- and di(Cι.6alkyl)amino(-CH2-CH2-0)n; one of R2a andR2 is cyanoCi-δalkyl, cyanoC2^alkenyl, Ar3Cι-6alkyl, (Ar3)(OH)Cι-6alkyl, N(R8aR8b)C1-6alkyl, Ar3C2-6alkenyl, Het-C2-6alkenyl, Ar3aminoCι^alkyl, Het-aminoCι-6alkyl, Het-Ci^alkylamino- Ci^alkyl, Ar thioCι-6alkyl, Het-thioCi^alkyl, Ar sulfonylCι^alkyl, Het-sulfonyl- C1-6alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het- (CH2)naminocarbonyl, Ar3carbonylarnino, Het-carbonylamirio, ^(CH^αCa bonylamino, Het-(CH2)ncarbonylamino or Ar3(CH2)namino; and the other one of R2*1 and R2b is hydrogen; in case R2a is hydrogen, then R3 is hydrogen; in case R2 is hydrogen, then R3 is hydrogen or
R4a and R4 can be the same or can be different relative to one another, and are each independently hydrogen or C^aU yl; or
R4a and R4b taken together may form a bivalent radical of formula -(CH2)S- wherein s is 4 or 5;
R5 is hydrogen or
R6 is hydrogen or C^alkyl optionally substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR^R715, C3-7cycloalkyl, Ar2, hydroxy, C1- a!koxy, C^alkylthio, Ar^-oxy-, Ar^thio-, Ar2(CH2)nthio, hydroxycarbonyl, aminocarbonyl, C1-4alkyl- carbonyl, Ar (CH2)ncarbonyl, aminocarbonyl- oxy, Ar2carbonyloxy, Ar2(CH2)nCarbonyloxy, carbonyl(CH2)noxy, mono- or di(Ci alkyl)aminocarbonyl, mono- or di(Cι-4alkyl)- aminocarbonyloxy, aminosulfonyl, mono- or (h(Ci.4alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrroUdinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl ,pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with one or two radicals selected from oxo and Chalk !; R6a is Cι_6alkyl substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR^R7", C3-7cycloalkyl, Ar2, hydroxy, C1- alkoxy, Ar2(CH2)noxy, Ar2(CH2)nthio, hydroxycarbonyl, am nocarbonyl, Ar2ca bonyl, Cι_4alkoxycarbonyl, Ar2(GH2)ncarbonyl, am nocarbonyloxy, C^alkylcarbonyl- oxy, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, mono- or di(Cι^alkyl)aminocarbonyl, mono- or di(Cι^alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(Cι-4alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with one or two radicals selected oxo and C^aU yl; R7a is hydrogen, Chalky!, formyl or Ci-ealkylcarbonyl; R is hydrogen, C1-6alkyl, formyl or Ci-ealkylcarbonyl; R8a is Ar3, Ci-ealkyl, hydroxyCi-6alkyl, Ci-ealkoxyCi-βalkyl, cyanoCi-galkyl, aminoCi-βalkyl, mono-or aminocarbonyl-Ci-6-alkyl, carboxyl-Ci-6-alkyl; R8b is Ar3, Ci-βalkyl, hydroxyCι-6alkyl, Cι-6alkoxyC1-6alkyl, cyanoC1-6alkyl, mono-or Ar3Cι-6alkyl, each n independently is 1, 2, 3 or 4; each m independently is 1 or 2; each p independently is 1 or 2; Ar1 is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from halo, hydroxy, d^alkyl, hydroxyCι.6alkyl, polyhaloC^alkyl, and Ar2 is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, amino, cyano, hydroxyCi-salkyl, polyhaloC^alkyl, aminoCi-ealkyl, Ci^alkyloxy, aminosulfonyl, aminocarbonyl, hydroxycarbonyl, C^alkylcarbonyl, mono- or di(Ci alkyl)amino, mono- or <h(d-4alkyl)aminocarbonyl, mono- or ch(d al l)ammosulfonyl, mono- or and d^alkoxycarbonyl; Ar3 is phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl, wherein said phenyl, naphtyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl may optionally and each individually be substituted with one or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, mercapto, amino, cyano, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Ar1, hydroxyd-δalkyl, polyhaloCi-βalkyl, cyanod-6alkyl, aminocarbonyl, Ci-βalkyloxy, Cι-6alkyltbio, AXoxy, AXthio, Ar1-amino, aminosulfonyl, ammocarbonyl-Cι-6alkyl, hydroxyl- carbonyl-Cι-6alkyl, hydroxycarbonyl, C^alkylcarbonyl, mono- or (H(d^alkyl)arnino, mono- or di(C1- alkyl)aminocarbonyl, mono- or Het is a heterocycle being selected from tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, dioxolanyl, pyrrolidinyl, pyrrolidinonyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl, each of said heterocycle may optionally be substituted with oxo, amino, Ar1, hydroxyd-ealkyl, mono- or di(d-6alkyl)arrrinoCi-6alkyl, mono- or di(Ci-6alkyl)amino, or with two d^alkyl radicals.
The invention also relates to the use of a compound of formula (I), or a prodrug,
N-oxide, addition salt, quaternary amitte, metal complex and stereochemically isomeric form thereof, for the manufacture of a medicament for inhibiting RSN replication. Or the invention relates to a method of inhibiting RSN replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (T), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof.
In a further aspect, this invention relates to novel compounds of formula (I) as well as methods for preparing these compounds.
The term prodrug as used throughout this specification and claims means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15) describing prodrugs generally, is hereby incorporated. Prodrugs are characterized by a good aqueous solubility and bioavailability, and are readily metabolized into the active inhibitors in vivo.
The terms 'd-ioalkanediyl optionally substituted with one or more substituents' and 'Ci-βalkyl optionally substituted with one or more substituents' such as used in the definition of G and respectively R6 or R6a are meant to comprise d-ioalkanediyl or Ci-βal yl radicals having two or more substituents, for example two, three, four, five or six substituents, in particular two or three substituents, further in particular two substituents. The upper limit of the number of substituents is determined by the number of hydrogen atoms that can be replaced as well as by the general properties of the substituents such as their bulkiness, these properties allowing the skilled person to determine said upper limit.
As used in the foregoing and hereinafter, as a group or part of a group, e.g. in polyhalod-ealkyloxy, is defined as mono- or polyhalo substituted Cι_6alkyl, in particular Ci-ealkyl substituted with up to one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Also included are perfluoro d-ealkyl groups, which are Ci-βalkyl groups whereion all hydrogen atoms are replaced by fluoro atoms, e.g. pentafluoroethyl. In case more than one halogen atom is attached to an alkyl group within the definition of polyhaloCi^alkyl, the halogen atoms may be the same or different.
Each of the monocyclic or bicyclic heterocycles in the definition of R1 may optionally be substituted with 1 or where possible more substituents, such as 2, 3, 4 or 5, substituents. In particular, said heterocycles may optionally be substituted with up to 4, up to 3, up to 2 substituents, or up to 1 substituent.
Each Ar1 or Ar2 may be unsubstituted phenyl or phenyl substituted with 1 or more substituents, such as 5 or 4 substituents or, which is preferred, up to 3 substituents, or up to two substituents, or with one substituent. Ar3 is phenyl, naphthalenyl, 1,2,3,4- tetrahydro-naphthalenyl or indanyl, which each may optionally with one or more substituents, such as 5 or 4 substituents or, which is preferred, up to 3 substituents, or up to two substituents, or with one substituent. A hydroxyCi-βalkyl group when substituted on an oxygen atom or a nitrogen atom preferably is a hydroxyC2-6alkyl group wherein the hydroxy group and the oxygen or nitrogen are separated by at least two carbon atoms.
R6 or Rfe can be Ci-βalkyl substituted with one or more substituents selected from NR7aR7 , hydroxy, Ar2-oxy-, AXthio-, Ar2(CH2)noxy, Ar2(CH2)nthio, amino carbonyloxy, C1- alkylcarbonyloxy, Ar2(CH2)nCarbonyloxy, Cι^alkoxycarbonyl(CH2)nθxy, mono- and ώ(Cι.4alkyl)amino- carbonyloxy. In that instance C^aUcyl preferably has at least two carbon atoms (i.e. C2-6alkyl) and the said substituents are not substituted on the carbon atom linked to the nitrogen bearing Q.
As used herein C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1 -methylethyl, butyl and the like; C2^alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyL 1 -methylethyl, butyl and the like; Ci-βalkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for and pentyl, hexyl, 2-methylbutyl and the like.
As used herein C2-6alkenyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having at least one double bond, and preferably having one double bond, and further having from 2 to 6 carbon atoms such as ethenyl, propenyl, buten- 1 -yl, buten-2-yL penten- 1 -yl, penten-2-yl, hexen- 1 -yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-l-yl and the like.
C3_7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
C2.5alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like, C^alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C^alkanediyl is meant to include C^alkanediyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like; Cj.jQalkanediyl is meant to include C^alkanediyl and the higher homologues thereof having from 7 to 10 carbon atoms such as, for example, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl and the like.
As used herein before, the term (=O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom. The term (=N-OH) forms a hydroxyimine moiety when attached to a carbon atom.
The term halo is generic to fluoro, chloro, bromo and iodo.
It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3 -pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.
When any variable occurs more than one time in any constituent, each definition is independent.
Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or similar term is meant to include the compounds of general formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms. An interesting subgroup of the compounds of formula (I) or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms of the compounds of formula (I).
It will be appreciated that some of the compounds of formula (I) may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term "stereochemically isomeric forms" as used hereinbefore defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.
Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantio- mers of the basic molecular structure of said compound All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure1 concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.
Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl- tartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
For some of the compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines, or metal complexes and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not experimentally determined. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohahc acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), maionic, succinic (i.e. butane- dioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, j3-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or a ine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hytobamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifiuoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
It will be appreciated that the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their ,tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Any subgroup of compounds of formula (I) specified herein is meant to also comprise the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of this subgroup of compounds of formula (I).
One embodiment of the present invention concerns compounds of formula (T-a):
wherein Q, R5, G, R1 and R b are as specified above in the definitions of the compounds of formula (I) or as in any of the subgroups of compounds specified herein.
Another embodiment of the present invention concerns compounds of formula (I-b): wherein Q, R , G, R , R and R are as specified above in the definitions of the compounds of formula (I) or as in any of the subgroups of compounds specified herein.
One particular embodiment of the present invention concerns compounds of formula
wherein Q, R5, G and R1 are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein; and
Alk is d-ealkanediyl;
R8chas the same meanings of R8a, and also maybe hydrogen;
R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
Another particular embodiment of the present invention concerns compounds of formula (I-b-1):
wherein Q, R5, G, R1 and R3 are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein; and
Alk is Ci-βalkanediyl;
R8c has the same meanings of R8a, and also may be hydrogen;
R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof. Another embodiment of the present invention concerns compounds of formula (I-c):
wherein t, G, the definition of the compounds of formula (I), or as in any of the subgroups of compounds specified herein.
Another embodiment of the present invention concerns compounds of formula (I-d):
wherein t, R5, R6, G, R1 and R2b are as specified above or as in any of the subgroups of compounds specified herein.
Another embodiment of the present invention concerns compounds of formula (I-e):
wherein t, R5, R6, G, R1, R2" andR3 are as specified above or as in any of the subgroups of compounds specified herein.
Still further embodiments comprise compounds of formula (I-c), (I-d) or (I-e) wherein t is 2, i.e. compounds of formulae
wherein Q, t, R5, G, R1, R23, R , R3 are as specified above or as in any of the subgroups of compounds specified herein.
Another embodiment of the present invention concerns compounds of formula (I-d-2):
wherein R5, R6, G andR1 are as specified abpve or as in any of the subgroups of compounds specified herein; and t is 1, 2 or 3; preferably t is 2;
Alk is C1-6alkanediyl;
R8c has the same meanings of R8a, and also may be hydrogen;
R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
Another embodiment of the present invention concerns compounds of formula (I-e):
wherein R5, R6, G, R1 and R3 are as specified above or as in any of the subgroups of compounds specified herein; and t is 1, 2 or 3; preferably t is 2;
R8c has the same meanings of R8a, and also may be hydrogen; R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof.
Further preferred subgroups are those wherein Alk is ethylene or methylene, more preferably wherein Alk is methylene.
In (I-a-1), (I-b-1), (I-d-2) or (I-e-2) R8c preferably is hydrogen, hydroxyd-βalkyl, aminocarbonyl-C1-6alkyl.
In (I-a-1), (I-b-1), (I-d-2) or (I-e-2): (a) R9, R10, R11 preferably and independently from one another are hydrogen, halo, hydroxy, mercapto, amino, cyano, Chalky!, d-βalkenyl, C^alkynyl, Ar1, hydroxyCi-δalkyl, CF3, aminod-όalkyl, cyanoCι-6alkyl, aminocarbonyl, d-βalkylthio, AXoxy, AXthio, AXamino, aminosulfonyl, aminocarbonyl-Cι_6alkyl, hydroxycarbonyl,
(b) R9, R10, R11 more preferably and independently from one another are hydrogen, halo, hydroxy, mercapto, cyano, d-ealkyl, C2^alkenyl, d-βalkynyl, Ar1, hydroxy- d-βalkyl, CF3, aminoCι-6alkyl, cyanoCi-ealkyl, aminocarbonyl, AXoxy, AXthio, Ar1 -amino, aminosulfonyl, aminocarbonyl- hydroxycarbonyl-C1-6alkyl,
(c) R9, R10, R11 more preferably and independently from one another are halo, C1-6alkyl or hydroxyCi-ealkyl; or
(d) R9, R10 more preferably are as in (a), (b) or (c) and R11 is hydrogen; or (e) R9, R10 more preferably and independently from one another are Chalky! or hydroxy-d-ealkyl; and R11 is hydrogen; or
(f) R9, R10 still more preferably are Ci-βalkyl and R11 is hydrogen; or
(g) R9 is C1-6alkyl, R10 is hydroxy-d-6alkyl and R11 is hydrogen.
It is to be understood that the above defined subgroups of compounds of formulae (I-a), (I-b), etc. as well as any other subgroup defined herein, are meant to also comprise any prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of such compounds. Particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein G is
Ci-ioalkanediyl, more in particular wherein G is methylene.
Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R1 is other than Ar1; or wherein
(b) R1 is Ar1 or a monocyclic heterocycle, which is as specified in the definitions of the compounds of formula (I) or any of the subgroups thereof.
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(c) R1 is pyridyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, carboxyl, d-βalkyl, Ci-βalkyloxy, Ci-βalkylthio, Ar1, Ar1Cι-6alkyl, mono-or chχd-6alkyl)amino, mono-or Ci-ealkyl-SOa-NR48-, AXsOa- R4*-, C1-6alkyloxycarbonyl, -C(=O)-NR4aR4b, HO(-CH2-CH2-O)„-, halo(-CH2-CH2-O)n-, d-6alkyloxy(-CH2-CH2-O)„-, Ar1Cι-6alkyloxy(-CH2-CH2-O)n- and mono-or di(Cι-6alkyl)amino(-CH2-CH2-0)n-; or more in particular
(d) R1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy, and (C1-6alkyloxy)Cι-6alkyloxy; preferably wherein
(e) R1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy, or wherein
(f) R1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy and Ci-βalkyl; more preferably wherein (g) R1 is pyridyl substituted with hydroxy and Ci-ealkyl; or more preferably wherein (h) R1 is pyridyl substituted with hydroxy and methyl; or wherein (i) R1 is 3-hydroxy-6-methylpyrid-2-yl.
Further embodiments comprise those compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein
(j) R1 is Ar1, quinolinyl, benzimidazolyl, a radical of formula pyrazinyl, or pyridyl; or wherein
(k) R1 is Ar1, quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl or pyridyl; wherein each of the radicals in (j) and (k) may optionally be substituted with the substitutents specified in the definition of the compounds of formula (I) and in particular pyridyl may be substituted as specified above in (a) to (i); or more specifically wherein
(1) R1 is Ar1, qumolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl or pyridyl, wherein each of these radicals may optionally be substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, or more specifically wherein (m) R1 is Ar1, quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl or pyridyl, wherein each of these radicals may optionally be substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci-βalkyl, benzyloxy; or more specifically wherein (n) R1 is phenyl optionally substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, Ci-βalkyl, quinolinyl; a radical (c-4) wherein m is 2, optionally substituted with up to two radicals selected from d-ealkyl; benzimidazolyl optionally substituted with Ci-ealkyl; pyridyl optionally substituted with one or two radicals selected from hydroxy, halo, C1-6alkyl, benzyloxy and pyrazinyl optionally substituted with up to three radicals selected from d-βalkyl; or pyridyl substituted or optionally substituted as specified above in (a) - (i); or wherein (o) R1 is phenyl optionally substituted with one or two radicals selected from the group consisting of halo, hydroxy, C^alkyl, Ci^alkyloxy; (p) R1 is quinolinyl; (q) R1 is a radical (c-4) wherein m is 2, optionally substituted with up to two radicals selected from Chalky!; (r) R1 is benzimidazolyl optionally substituted with Ci-βalkyl; pyridyl optionally substituted with one or two radicals selected from hydroxy, halo, benzyloxy and Ci-ealkyloxy, (s) R1 is pyrazinyl optionally substituted with up to three radicals selected from Cι-6alkyl.
Preferred subgroups of compounds of formula (I) or any of the subgroups of compounds of formula (I) are those wherein G is a direct bond or methylene and R1 is as specified above in (a) - (s). Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein G is a direct bond and R1 is a radical (c-4), in particular wherein m is 2, optionally substituted with up to two radicals selected from Ci-βalkyl. Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein or G is methylene and R1 is as specified above in (a) — (s), but is other than a radical (c-4).
A particular embodiment of the present invention concerns compounds of formula (I) or of any of the subgroups of compounds of formula (I) specified herein wherein (a) one of R2a and R3a is selected from cyanoCi-ealkyl, cyanoC2-6alkenyl, Ar3Cι-6alkyl, N(R8aR8b)C1-6alkyl, Ar3C2-6alkenyl, Ar3aminoC1-6alkyl, Het-aminoC1.6alkyl, Het-d-ealkylamino- Ci-βalkyl, A thiod-βalkyl, Het-thioC1-6alkyl, Ar3sιdfonylCι-6alkyl, Het-sulfonyl- Ci-βalkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het- (CH2)naminocarbonyl, Ar3carbonylamino, Ar^CH^namino; and the other one of R2a andR2 is hydrogen; or
(b) one of R2a and R3a is selected from cyanoCi-ealkyl, cyanod^alkenyl, Ar3Cι-6alkyl, (Ar3)(OH)Cι^alkyl, Het-d-ealkyl, N(R8aR8b)C1-6alkyϊ, Ar3C2-6alkenyl, Ar3aminoC1-6alkyl, Het-aminoCi-βalkyl, Het-Ci-ealkylanunoCi-ealkyl, Ar3thio- C^alkyl, Ar3aminocarbonyL Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het- (CH2)naminocarbonyl, Ar3carbonylamino, Ar3(CH2)namino; and the other one of R2a andR2b is hydrogen; or
(c) one of R2a and R3a is selected from cyanoCi ^alkyl, Ar3Cι-ealkyl, Het-Ci-βalkyl, N(R8aR8b)Cι.6alkyl, Ar3C2-6alkenyl, Het- Cι-6alkylaminoCι^alkyl, Ar3thiod^alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl; and the other one of R2a and R2b is hydrogen; or
(d) one of R a and R3 is selected from cyanoCi-ealkyl, Ar3C1-6alkyl, Het-d^alkyl, Ar3 aminocarbonyl; and the other one of R28 and R2 is hydrogen; or
(e) one of R2a and R3a is selected from Ar3C1-6alkyl, N(R8aR8 )C^alkyl, Ar3C2-6alkenyl, Ar3aminoCι-6alkyl; and the other one of R2*1 and R2b is hydrogen; or (f) one of R2a and R3a is selected from N(R8aR8 )C1-6alkyl, Ar3aminoC1-6alkyl; and the other one of R28 and R b is hydrogen; and for any of (a) - (f) in case R2 is hydrogen then R3 is hydrogen; in case R2 is hydrogen then R3 is hydrogen or or preferably then R3 is hydrogen.
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein R5 is hydrogen.
Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is Ar2.
Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is R6a.
Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is pyrrolidinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6; in particular wherein Q is piperidinyl substituted with R6. Preferably the R6 group is substituted on the nitrogen atom of the said pyrrolidinyl, piperidinyl or homopiperidinyl. More preferably the said pyrrolidinyl, piperidinyl or homopiperidinyl is linked to the -N(R5)- moiety via a 3-yl or in particular via a 4-yl link.
Interesting subgroups of compounds are those compounds of formula (I) or of any of the subgroups specified herein, wherein Q is R6a, wherein
(a) R6a is substituted with two substituents or, preferably, with one substituent, each independently selected from the group consisting of trifluoromethyl, NR7aR7b, Ar2, hydroxy, C^alkoxy, Ar2(CH2)nθxy, hydroxycarbonyl, arninocarbonyl, C1-4alkoxycarbonyl, Ar2(CH2)nCarbony aminocarbonyloxy, C1-4alkylcarbonyloxy, Ar2carbonyloxy, mono- or aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and d-ealkyl; or in particular wherein
(b) R6a is C1-6alkyl substituted with one substituent and, optionally with a further substituent which is hydroxy, wherein said substituent is trifluoromethyl, NR^R , Ar2, hydroxy, Ar2(CH2)noxy, hydroxycarbonyl, aminocarbonyl, Ar2(CH2) carbonyl, aminocarbonyloxy, AΛarbonyloxy, mono- or aminosulfonyl, mono- or di(Ci alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of
» said heterocycle may optionally be substituted with with one or two radicals selected from oxo and C1-6alkyl; or further in particular
(c) R6a is Ci-βalkyl substituted with NR7 R7b, Ar2, hydroxy, C^alkoxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl C1- alkoxycarbonyl, or C^alkyl substituted with two hydroxy radicals, or Ci-βalkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two C^aUcyl radicals; or further in particular (d) R6a is C1-6alkyl substituted with NR^R , Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or Ci-βalkyl substituted with two hydroxy radicals, or d-βalkyl substituted with a heterocycle selected from dioxolanyl, pyrroUdinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two C1-6alkyl radicals; or further in particular
(e) R6a is Chalky! substituted with Ar2 or hydroxy, or d^alkyl substituted with two hydroxy radicals, or substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, wherem each of said heterocycle may optionally be substituted with one or two C^aUcyl radicals; or preferably (f) R6a is d-βalkyl substituted with Ar2 or hydroxy, or Ci-βalkyl substituted with two hydroxy radicals, or Chal y! substituted with diC^alkyl-dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-Cι^alkyl-piperazinyl; or preferably (g) R6a is substituted with two hydroxy radicals, or substituted with piperidinyl or with piperazinyl; or more preferably
(h) R6a is d^alkyl substituted with Ar2 or d^alkyl substituted with piperidinyl or with piperazinyl. Preferably in (a) - (h) in the previous paragraph the radicals pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl are linked by their nitrogen atom to the Ci-βalkyl on which they are substituted.
Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is pyrrofidinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6; wherein
(a) R6 is hydrogen or optionally substituted with two substituents or, preferably, with one substituent, each independently selected from the group consisting of trifluoromethyl, Ar2(CH2)noxy, hydroxycarbonyl, aminocarbonyl, C1- alkylcarbonyl, Ar2(CH2)nCarbonyl, aminocarbonyloxy, mono- or di(C1- alkyl)aminocarbonyl, aminosulfonyl, mono- or di(d- alkyι)- aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and or in particular
(b) R6 is hydrogen or C^aUcyl optionally substituted with one substituent and, optionally with a further substituent which is hydroxy, wherein said substituent is trifluoromethyl, hydroxycarbonyl, aminocarbonyl, C1- alkylcarbonyl, Ar2(CH2)n- carbonyl, aminocarbonyloxy, mono- or di(C1- alkyl)aminocarbonyl, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and or further in particular
(c) R6 is hydrogen or Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl, or Ci-ealkyl substituted with two hydroxy radicals, or Ci-ealkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two d-βalkyl radicals; or further in particular (d) R6 is hydrogen or d-ealkyl optionally substituted with NR7aR7b, Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, arninosulfonyl or d^alkyl substituted with two hydroxy radicals, or C^aU yl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two Ci-δalkyl radicals; or further in particular wherein
(e) R6 is hydrogen or Cι-6alkyl optionally substituted with Ar2, hydroxy, aminocarbonyl or aminosulfonyl, or Ci-βalkyl substituted with two hydroxy radicals, or Ci-βalkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with one or two Ci-βalkyl radicals; or preferably
(f) R6 is hydrogen or d-βalkyl optionally substituted with Ar2, hydroxy, aminocarbonyl, aminosulfonyl, or d-βalkyl substituted with two hydroxy radicals, or d-βalkyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkyl- piperazinyl; or preferably
(g) R6 is hydrogen or d^alkyl optionally substituted with Ar2, hydroxy, aminocarbonyl or aminosulfonyl; or preferably
(h) R6 is hydrogen or d-ealkyl substituted with Ar2 or Chalky! substituted with piperidinyl or with piperazinyl; or
(i) R6 is Ci-ealkyl.
Preferably in (a) - (h) in the previous paragraph, the radicals pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl are linked by their nitrogen atom to the d-βalkyl on which they are substituted.
Further particular subgroups of the compounds of formula (I) are those compounds of fβπhula (I), or any subgroup of compounds of formula (I) specified herein, wherein R7a and R76 are hydrogen or or preferably wherein R7a and R71* are hydrogen.
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R8a is Ar3, Chalky!, hydroxyd^alkyl, Ci^alkoxyC^alkyl, cyanoCι-6alkyl, aminod-ealkyl, mono-or Ar3Cι-6alkyl, Het-Ci-βalkyl, aminocarbonyl-Cι-6-alkyl, carboxyl-d-e-alkyl; and R81' is Ar3; or
(b) R8a is Ar3, Chalky!, Het-Ci-βalkyl, amino- carbonyl-d-6-alkyl; and R8b is Ar3; or
(c) R is hydroxyd-ealkyl, aminocarbonyl-d-6-alkyl; and R > 8b : is A k_r3 ;. or
(d) R8a is Ar3 and R8b is Ar3; or (e) R8a is d^alkyl, hydroxyd-ealkyl, Ar3C1-galkyl, Het-C1-6alkyl, aminocarbonyl- In particular, Ar1 is phenyl or phenyl substituted with 1, 2, 3 substituents or with 1, 2 substituents selected from those mentioned in the definition of the compounds of formula (I) or of any subgroup thereof.
In the group of compounds of formula (I) or in any of the subgroups of compounds of formula (I):
(a) Ar1 preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo, hydroxy, Cι-6alkyl, hydroxyCi_6alkyl, trifluormethyl, and Ci-βalkyloxy; (b) Ar1 more preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo, hydroxy, Ci-salkyl and Ci-βalkyloxy; (c) Ar1 more preferably is phenyl or phenyl substituted with up to 3 substituents, or with up to 2 substituents, or with one substituent, selected from halo and d^alkyl.
In particular, Ar2 is phenyl or phenyl substituted with 1, 2, 3 substituents or with 1, 2 substituents selected from the group consisting of those mentioned in the definition of the compounds of formula (I) or of any subgroup thereof.
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Ar2 is as defined for Ar1.
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Ar3 is phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl, or preferably wherein Ar3 is phenyl, naphthalenyl or indanyl; wherein said phenyl may optionally and each individually be substituted with one or more, such as 2, 3 or 4, substituents selected from the group consisting of substituents of Ar3 in the definitions of the compounds (I).
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein (a) Ar3 is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, mercapto, amino, cyano, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Ar1, hydroxyd^alkyl, CF3, aminoC^alkyl, cyanoCi-δalkyl, aminocarbonyl, Ci-βalkyloxy, d-ealkylthio, AXoxy, AXthio, Ar1 -amino, aminosulfonyl, aminocarbonyl-d-ealkyl, hydroxycarbonyl-d-βalkyl, hydroxycarbonyl, or C alkoxycarbonyl; or wherein
(b) Ar3 is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, mercapto, cyano, Chalky!, C2-6alkenyl, C2-6alkynyl, Ar1, hydroxyd-βalkyl, CF3, aminoCi-ealkyl, cyanoC1-6alkyl, aminocarbonyl, Cι-6alkylthio, Ar1-oxy, AXthio, AXamino, aminosulfonyl, aminocarbonyl-Ci-ealkyl, hydroxycarbonyl-Ci-βalkyl, or wherein
(c) Ar3 is phenyl optionally substituted with one, two or three substituents selected from halo, Ci^alkyl or hydroxyd-ealkyl; or
(d) Ar3 is phenyl substituted with one, two or three substituents selected from halo, Ci-ealkyl or hydroxyC1-6alkyl; or
(e) Ar3 is phenyl optionally substituted with one, two or three substituents selected from halo, or hydroxyCi-ealkyl; or (f) Ar3 is phenyl substituted with one, two or three substituents selected from halo, d-βalkyl or hydroxyd-όalkyl; or (g) Ar3 is phenyl substituted with one or two substituents selected from halo, or hydroxyCi-ealkyl; or (h) Ar3 is phenyl optionally substituted with one or two substituents selected from Cnjalkyl or hydroxyCι-6alkyl.
In particular Ar3 is as defined for Ar2, more in particular Ar3 is as defined for Ar1.
Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) Het is tefrahydrofuranyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydroquinolinyl, quinohnyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl, which may optionally be substituted with oxo, amino, Ar1, C1-4alkyl, hydroxyd-βalkyl, A^d^alkyl, mono- or di(d-6alkyl)aminoCι-6alkyl, mono- or and optionally further with one or two radicals; or
(b) Het is tetrahydrofuranyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pvrimidinyl, tetoahycboquinolinyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl, which may optionally be substituted with oxo, amino, Ar1, Ci^alkyl, aminoCi^alkyl, hydroxyCi-ealkyl, and optionally further with one or two d^alkyl radicals; or (c) Het is furanyl, thienyl, imidazolyl, pyrazolyl, isoxazolyl, morpholinyl, pyrimidinyl, benzodioxolyl, quinolinyl, indolinyl, which may optionally be substituted with hydroxyCi-6alkyl or with one or two radicals; or (d) Het is furanyl, thienyl, imidazolyl, pyrazolyl, isoxazolyl, moroholinyl, pyrimidinyl, benzodioxolyl, quinolinyl, indolinyl, which may optionally be substituted with hydroxyd-6alkyl or with one or two radicals; or
(e) Het is furanyl, imidazolyl, moipholinyl, benzodioxolyl, quinolinyl, indolinyl, which may optionally be substituted with hydroxyCι-6alkyl or with one or two d^alkyl radicals; or
(f) Het is morpholinyl, which may optionally be substituted with one or two radicals; or
(g) Het is morpholinyl.
Preferred compounds are those compounds listed in tables 1 through 5, more in particular the compound numbers 1 to 77, 138, 143 to 165 and 171 to 177.
The compounds of formula (I) or any of the subgroups thereof can be prepared as in the following reaction schemes.
In this schemes Q, G, R1, R2" , R2b , R3a , R3b R5 have the meanings defined above for the compounds of formula (I) or of any of the subgroups thereof. W is an appropriate leaving group, preferably it is chloro or bromo. The reaction of this scheme is typically conducted in a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHC13, toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like.
The compounds of formula (I) wherein Q is apyrrolinyl, piperdinyl or homopiperidinyl group substituted with R6 which is other than hydrogen, i.e. R6a, which are represented by formula (I-c-1), can be prepared as in the following reaction scheme.
In this scheme G, t, R1, R2a, R2 , R3, R5 have the meanings defined above for the compounds of formula (I) or of any of the subgroups thereof. W is an appropriate leaving group, preferably it is chloro or bromo. The reaction of this scheme can be conducted in a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHC13, toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like. A base may be added to pick up the acid that is liberated during the reaction. If desired, certain catalysts such as iodide salts (e.g. KI) maybe added Intermediates (TV) can also be converted to compounds (I-c-1) with a reductive N-alkylation reaction starting from an aldehyde or ketone * =0 (V-a), wherein R6a has the same meaning as R63 provided that it has one hydrogen atom less. This reductive alkylation is done in a suitable solvent, e.g. an alcohol, using hydrogen in the presence of a metal catalyst such as Pd or NaBH3CN.
Some of the compounds of formula (I) can also be prepared starting from precursors of the compounds of formula (I) using appropriate functional group transformation reactions.
Precursors of the compounds of formula (I) for example are those wherein R2a or R2 is Ci- alkoxycarbonyl or substituted with which can be reduced, e.g. with LiAlHU, to the corresponding compounds of formula (I) wherein R2a or R2b is The latter group can be oxidized with a mild oxidant to an aldehyde group, e.g. with MnO2, which can further be derivatized with amines, e.g. with a reductive amination process, to the corresponding mono(derivatizedC1-6aIkyl)- amines. The latter can be alkylated or arylated to alkylamines wherein R23 or R2b has formula -Alk-NR8aR8b. Alternatively precursors of the compounds of formula (T) wherein R28 or R2 is hydroxyd^alkyl can be converted to the corresponding haloCi-δalkyl compounds, e.g. by treatment with a suitable halogenating agent such as SOCl2, which compounds subsequently are reacted with an amine or amine derivative. This reaction sequence is illustrated by the following schemes in which R12 represents a Chalky! radical, which preferably is methyl or ethyl. This reaction sequence may be done starting from (Vll-a) or (VTI-b) separately but also can be done using a mixture of (VTI-a) and (VTI-b) and subsequently separating the reaction products either at the end of the reaction sequence or in an intermediate step.
alkyiation
arylatioπ (i-g-1)
(i-g-1)
Or starting from (VH-b):
reduction
(Vll-b) (VII l-b) oxidation
(IX-b) (i-f-2) alkylation arylation
(i-g-2)
(l-g-2) Precursors of the compounds of formula (I) wherein R2a or R2b is an aldehyde can be converted to the corresponding compounds wherein R2a or R2b is substituted C^alkenyl (I-g-1) or (I-g-2), by a Wittig reaction or a Wittig-Horner reaction. In the former instance a Wittig type reagent is used, such as a triphenylphosphoniumyUde in a suitable reaction-inert solvent such as an ether, starting from triphenylphosphine and a halo derivative. The Wittig-Horner reaction is performed using a phosphonate, such as e.g. a reagent of formula ά (Cι-6alkyloxy)-P(=O)-CH2-CH -CN in the presence of a base, preferably a strong base, in an aprotic organic solvent. Compounds wherein R2a or R3a is substituted Qz-salkenyl can be reduced to the corresponding compounds wherein R2a or R3a is substituted C2-6alkyl (I-i-1) or (I-i-2), e.g. with hydrogen in the presence of a noble metal catalyst such as Pd/C. The cyano group in turn can be reduced to the corresponding melhyleneamine (-CH2-NH2) group with hydrogen in the presence of a catalyst such as Raney Ni, in a suitable solvent such as methanol/ammonia. This reaction yields compounds (I-j-1) and (I-j-2) which can be mono-alkylated or double alkylated to yield compounds (I-k-1), (I-k-2) and (1-1-1), (1-1-2). These alkylations may be done by a reductive alkylation reaction using an aldehyde or ketone in the presence of hydrogen and a catalyst (yielding mono-alkyl derivatives) or with suitably substituted alkyl halides (yielding mono- or dialkyl derivatives). These reactions are depicted in the following reaction schemes. In these schemes R28"1 represents CN, Ar3 or Het, Alk1 represents C -6alkanediyl radicals (which are as Ci-ealkanediyl, but having from 4 — 6 carbon atoms), R and R , 8b have the same meanings as defined in this specificationa and claims, but preferably are other than Ar3.
alkylation arylation
alkylation arylation (1-1-1 )
(IX-b) (i-g-2)
(l-j-2)
alkylation arylation
(l-k-2) alkylation arylation
(1-1-2)
Compounds of formula (T) wherein R2a or R is an aldehyde or Ci^alkyl substituted with a keto or an aldehyde can also be derivatized with a Grignard type of reaction to introduce aryl or alkyl groups. An additional aspect of the present invention concerns the fact that some of the compounds identified as precursors of the compounds of formula (I), are novel compounds.
In particular the compounds of formula (NH-a), (VH-b), (VHI-a), (Nlϊl-b), (LX-a), (D -b), (I-f-1), (I-f-2), (I-g-1), (I-g-2) wherein G, R1, R2a, R2 , R3, R5, R8a, R815, R12 are as defined above in the definitions of the compounds of formula (I) or in any of the subgroups thereof, and wherein Q is pyrrolidinyl, piperidinyl or homopiperidinyl, substituted on their nitrogen with a radical R6 which is d-βalkyl optionally substituted with one or more, preferably one or two, substituents each independently selected from the group consisting of trifluoromethyl, C3- cycloalkyl, Ar2, hydroxy, AXthio-, Ar2(CH2)noxy, hydroxycarbonyl, aminocarbonyl, Ar2(CH2)nCarbonyl, aminocarbonyloxy, Ar2(CH2)nCarbonyloxy, carbonyl, mono- or di(d-4alkyl)arιιinocarbonyloxy, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with one or two substituents selected from oxo or C^aU yl; and wherein said R6can be represented by R615, as well as the pharmaceutically acceptable salt forms thereof, and the possible stereoisomeric forms thereof, are novel compounds.
Of particular interest are any of the groups of novel compounds specified in the previous paragraph wherein:
(a) R6b is Ci-ealkyl optionally substituted with two substituents or, preferably, with one substituent, each independently selected from the group consisting of trifluoromethyl, Ar2, hydroxy, Ci ^alkoxy, Ar2(CH2)noxy, hydroxycarbonyl, aminocarbonyl, C1- alkylcarbonyl, C1- alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyloxy, Ar bonyloxy, mono- or (C1-4alkyl)amino- carbonyl, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and Ci-βalkyl; or in particular
(b) R611 is Ci-ealkyl optionally substituted with one substituent and, optionally with a further substituent which is hydroxy, wherein said substituent is trifluoromethyl, Ar2, hydroxy, Cι-4alkoxy, Ar2(CH2)noxy, hydroxycarbonyl, aminocarbonyl, C1-4alkylcarbonyl, Cι-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyloxy, C1- alkylcarbonyloxy, Ar2carbonyloxy, mono- or di(Cι^all^l)aminocarbonyl, aminosulfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and or further in particular (c) R615 is Ci-βalkyl optionally substituted with Ar2, hydroxy, C^aU-oxy, hydroxy- carbonyl, aminocarbonyl, arninosulfonyl, d^alkoxycarbonyl or dialkyl substituted with two hydroxy radicals, or C1-6alkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two Ci-βalkyl radicals; or further in particular (d) R615 is d-δalkyl optionally substituted with Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or C^aUcyl substituted with two hydroxy radicals, or Ci-βalkyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two Ci-βalkyl radicals; or further in particular wherein
(e) R615 is C1-6alkyl optionally substituted with Ar2, hydroxy, aminocarbonyl or arninosulfonyl, or substituted with two hydroxy radicals, or Ci-βalkyl substituted with a heterocycle selected from dioxolanyl, pyrroUdinyl, piperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with one or two Cι_6alkyl radicals; or preferably
(f) R^ is Ci-6alkyl optionally substituted with Ar2, hydroxy, aminocarbonyl, aminosulfonyl, or substituted with two hydroxy radicals, or dialkyl substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-C^alkyl-piperazinyl; or preferably (g) R61' is Chalky! optionally substituted with Ar2, hydroxy, aminocarbonyl or aminosulfonyl; or preferably (h) R^ is Cwalkyl.
Preferably in (a) — (h) in the previous paragraph the radicals pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl are linked by their nitrogen atom to the dialkyl on which they are substituted Moreover these compounds have found to possess antiviral properties, in particular to possess RSV inhibitory activity. Of particular interest are the compounds of formula (Nπ-a), (VH-b), (Nπi-a) and (VIH-b) wherein Q is 4-piρeridinyl wherein the ring nitrogen is substituted with a radical R6 which is Ci-ealkyl, as well as the pharmaceutically acceptable salt forms thereof, and the possible stereoisomeric forms thereof. As used herein, the terms 'pharmaceutically acceptable salt forms' and the 'stereoisomeric forms' have the meanings specified above in this specification.
Also the compounds of formula (VH-a), (VTI-b), (VHI-a), (VDI-b), (LX-a), (TX-b), (I-f-1), (I-f-2), (I-g-1), (I-g-2) wherein G, R1, R2a, R2 , R3, R5, R8a, R8 and R12 are as defined above in the definitions of the compounds of formula (I) or in any of the subgroups thereof, and wherein Q is R6 which is as specified in the previous paragraphs, as well as the pharmaceutically acceptable salt forms thereof, and the possible stereoisomeric forms thereof, are novel compounds. Moreover these compounds have found to possess antiviral properties, in particular to possess RSN inhibitory activity.
Of particular interest are those compounds mentioned in the previous paragraph wherein G, R1, R28, R2b, R3, R5, R 8a and R815 are as specified in any of the subgroups mentioned in this specification and claims. Preferred are those novel compounds mentioned in the previous paragraphs wherein G is d^alkanediyl, more preferably wherein G is methylene; and/or wherein R24, R2b, R3, R5 are all hydrogen; and/or R1 is pyridyl being substituted as outlined in this specification and claims, in particular R1 is pyridyl being substituted with one or two substituents selected from Cι-6alkyl and hydroxy.
Compounds of formula (I) may be converted into each other following art-known functional group transformation reactions, comprising those described hereinafter.
Νitro groups can be reduced to amino groups, which subsequently may be alkylated to mono- or dialkyla ino groups, or acylated to aiylcarbonylamino or alkylcarbonyl- amino and the like groups. Cyano groups may be reduced to aminomethylene groups, which similarly may be derivatized.
A number of the intermediates used to prepare the compounds of formula (I) are known compounds or are analogs of known compounds, which can be prepared following modifications of art-known methodologies readily accessible to the skilled person. A number of preparations of intermediates are given hereafter in somewhat more detail. (VI) (VII)
(VIII) (IX) (II)
In a first step, a diaminobenzene (VI) is cyclized with urea in a suitable solvent, e.g. xylene, to yield a benzimidazolone (VII). The latter is converted to a benzimidazole derivative (VHI) wherein is a leaving group as specified above, in particular by reaction of (VII) with a suitable halogenating agent, for example POCl3, and the resulting intermediate (VlJJL) is reacted with the amine derivative (IX) to obtain intermediate (II).
The same reaction sequence may be used to prepare other intermediates. For example the intermediates of formula (TV) can be prepared by reacting intermediates (IX) with an amine (X) wherein Q is a a pyrrolinyl, piperdinyl or homopiperidinyl group wherein the nitrogen is substituted with a protective group to yield precursors of (TV) which ca be converted to intermediates (TV) by removing the protective group. Suitable protecting groups for this purpose comprise alkyloxycarbonyl groups such as methoxy or efhoxycarbonyl, which can be removed with a base, or benzyl or benzyloxycarbonyl groups, which can be removed with hydrogen in the presence of a catalyst.
The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with, an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper- oxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo- peroxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tbutyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and rnixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter- current distribution, liquid chromatography and the like.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I), which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional ci stallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospeciflcally. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context is an amount sufficient to prophylaxictically act against, to stabilize or to reduce viral infection, and in particular RSV viral infection, in infected subjects or subjects being at risk of being infected. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I) as specified herein.
Therefore, the compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
The compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
Thus, the present invention also provides a pharmaceutical composition adapted for adrninistration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of adrrrinistration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
The compounds of formula (T) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV). A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
The in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31-42).
Due to their antiviral properties, particularly their anti-RSV properties, the compounds of formula (I) or any subgroup thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms, are useful in the treatment of individuals experiencing a viral infection, particularly a RSV infection, and for the prophylaxis of these infectionLS. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular the respiratory syncytial virus.
The compounds of the present invention or any subgroup thereof may therefore be used as medicines. Said use as a medicine or method of treatment comprises the systemic adrninistration to viral infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the RSV infection.
The present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly RSV infection.
The present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by RSV, said method comprising the administration of an anti-virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I), as specified herein.
In general it is contemplated that an antiviral effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections. Examples
The following examples are intended to illustrate the present invention and not to limit it thereto. The terms 'compound 1', 'compound 2', etc. used in these examples refers to the same compounds in the tables.
The compounds were identified by LC/MS using the following equipment:
LCT: electrospray ionisation in positive mode, scanning mode from 100 to 900 amu; Xterra MS C18 (Waters, Milford, MA) 5 μ , 3.9 x 150 mm); flow rate 1 rrJ/min. Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient from 100 % A for 3 min to 100% B in 5 min., 100% B for 6 rnin to 100 % A in 3 min, and equilibrate again with 100 % A for 3 min).
ZQ: electrospray ionisation in both positive and negative (pulsed) mode scanning from 100 to 1000 amu; Xterra RP C18 (Waters, Milford, MA) 5 μm, 3.9 x 150 mm); flow rate 1 ml/ in. Two mobile phases (mobile phase A: 85% 6.5mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) were employed to run a gradient condition from 10O % A for 3 min to 100% B in 5 min., 100% B for 6 min to 100 % A in 3 min, and equilibrate again with 100 % A for 3 min).
Example 1 Scheme A
a-5 A mixture of a-1 (0.166 mol) and urea (0.199 mol) in xylene (300 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature. The precipitate was filtered off, rinsed with xylene and diisopropyl ether, and then dried, yielding 32g of intermediate a-2 (93%, melting point: > 260°C).
A mixture of a-2 (0.073 mol) in POCl3 (150 ml) was stirred at 100°C. HCI cone, (around 1.5 ml) was added drop wise very carefully until the dissolution of a-2. The mixture was stirred at 120°C for 6 hours. The solvent was evaporated until dryness. The residue was taken-up in H2θ/ice, basified with K2CO3 (powder) and extracted with ethylacetate + 10% methanol. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness, yielding 13.5 g of intermediate a- 3 (83%, melting point: 178°C).
A mixture of a-3 (0.051 mmol) and a-4 (0.056 mol) was stirred at 160°C for 2 hours. The residue was taken-up in CH2CI2 H2O and basified with a 10% solution of K2CO3 in water. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/methanol H4OH 95/5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 15.3 g of intermediate a-5 (79%).
A mixture of a-5 (0.0396 mol), a-6 (0.059 mol) and K2CO3 (0.1584 mol) in CH3CN (180ml) was stirred and refluxed for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH2CI2. The organic layer was washed with H2O, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue (20g) was purified by column chromatography over silica gel (eluent: Toluene/ 2-propanol/NBUOH 85/15/1 ; 20-45 μm). Two fractions were collected and the solvent was evaporated, yielding 5.3g of fraction 1 (27%) and 6.3g of fraction 2 (32%). Fraction 1 was crystallized twice in 2-propanone/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 4.9g of intermediate a-7 (25%, melting point: 179°C). Fraction 2 was crystallized from 2-propanone/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 5.5g of intermediate a-8 (28%, melting point: 238°C).
LiAUL; (0.009 mol) was added portion wise to a mixture of a-7 (0.003 mol) in tetrahydrofuran (60 ml) at 5°C under N2 flow. The reaction was stirred at 5°C for 1 hour and then at room temperature for 12 hours. Ethyl acetate and H2O were added carefully and the aqueous layer was saturated with K2CO3 (powder). The organic layer was separated, dried (over MgSO ) and then filtered over celite. The filtrate was evaporated until dryness, yielding 1.3 g of intermediate a-9 (97%). The crude product was used directly in the next reaction step. Intermediate a-10 was prepared analogously to the procedure described for intermediate a-9.
A mixture of a-9 (0.0028 mol) and Pd/C 10% (2.5g) in CH3OH (40ml) was hydro- genated at 40°C for 12 hours under an 8 bar pressure, then filtered over celite. Celite was washed with a solution of CH3OH/tetrahydrofuran (50/50). The filtrate was evaporated until dryness, yielding 1.8g of intermediate a-11 (95%, melting point: 260°C).
HCHO 37% in water (0.0098 mol), NaBH3CN (0.0059 mol) then CH3CO2H (2ml) were added at room temperature to a mixture of a-11 (0.0049 mol) in CH3CN (50ml). The mixture was stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in ethanol (30ml) and a 5N solution of HCI in 2-propanol (4ml) was added. The mixture was stirred at 80°C for 8 hours. The solvent was evaporated until dryness. The residue was taken up in CH2CI2/K2CO3 10%. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue was crystallized from CH3OH/2-propanone/ CH3CN. The precipitate was filtered off and dried, yielding 1.65g of a-12 (88%). Part of this fraction (0.15g) was crystallized from CH3OH/2-propanone. The precipitate was filtered off and dried (melting point: 165°C).
SOCI2 (2.1ml) was added drop wise to a mixture of a-12 (0.O018 mol) in CH2CI2 (20ml) at 5°C. The mixture was stirred at 5°C for 1 hour, then at room temperature for 12 hours. The solvent was evaporated until dryness, yielding 0.93g of intermediate a-13 (100%). The crude product was used directly in the next reaction step.
A mixture of a-13 (0.0003 mol), a-14 (0.0005 mol) andK2CO3 (0.0019 mol) in dimethylformamide (30ml) was stirred at 80°C for 4 hours and poured into H2O. The aqueous layer was saturated with K2CO3 and extracted with CH2Cl2/CH3OH. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue (0.25g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH OH 90/10/1; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.05g, 24%) was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.042g of compound a-15 (20%, compound 1, melting point: 201°C).
Example 2 Scheme B
b-3
A mixture of b-1 (0.0028 mol) and MnO2 (2.5g) in CH2C12 (40ml) was stirred at room temperature for 12 hours, and then filtered over celite. Celite was rinsed with CH2C12. The filtrate was evaporated until dryness. The residue was taken up in 2-propanone. The precipitate was filtered off and dried, yielding 0.75g of intermediate b-2 (69%, melting point: 250°C).
Variant 1 : A mixture of b-2 (0.0001 mol), 3,5-dichloro aniline (0.0001 mol), BH3CN on solid support (0.0001 mol) and CH3CO2H (2 drops) in CH3OH (4ml) was stirred at room temperature for 24 hours. The solution was filtered. The filtrate was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: 87/12/1.5; 5μm). The pure fractions were collected and the solvent was evaporated, yielding 0.026g of 2-[6-[(3,5-dicMoro-phenylamino)- methyl]-2-(l-methyl-ρiρericr -4-ylammo)-b pyridin-3-ol (38%, compound 2).
Variant 2 : b-2 (0.0005 mol), NaBH3CN (0.0006 mol), and then CH3CO2H (0.2ml) were added at room temperature to a rnixture of 3 -methyl-aniline (0.0006 mol) in CH3CN (20ml). The mixture was stirred at room temperature for 12 hours. H2O was added. The mixture was saturated with K2CO3 (powder) and extracted with CH2Cl2/CH3OH. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue (0.3g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3θH/triethylamine; 90/10/0.1; 5μm). The pure fractions were collected and the solvent was evaporated. The residue (0.17g, 68%) was crystallized from CH3θH/2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.13g of 2-[6-[(l-ethyUdene-3-methyl- penta-2,4-dienylammo)-methyl]-2-(l-meth^ ylmethyl]-6-methyl-pyridin-3-ol (52%, compound 9, melting point: 141°C). Example 3 Scheme C
c"1 c-2
A mixture of c-1 (0.0018 mol), 2-methyl-thiophenol (0.002 mol) and K2CO3 (0.0077 mol) in CH3CN (70ml) was stirred at 50°C for 12 hours. The solvent was evaporated until dryness. The residue was taken up in H2O. The mixture was extracted with CH2CI2. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue (0.55g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OII/NH4OH 88/12/2; 15-40μm). The pure fractions were collected and the solvent was evaporated. The residue (0.35g, 39%) was crystallized from CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.32g of 6-methyl-2-[2-(l -methyl-piperidm-4-ylarnino)-6-m- tolylsulfanylmethyl-benzoinήdazol-l-ylmemyl]-pyridin-3-ol (compound 93, melting point: 202°C).
Example 4 Scheme D
d-1 d-2
In scheme D, R is defined as Ar3, Het1, Het1(CH2)nor Het1(CH2)n. Intermediate d-2 (melting point: 262°C) was prepared analogous to the procedure described for intermediate a-11. Intermediate d-3 was prepared analogous to the procedure described for intermediate a-12.
A mixture of d-3 (0.0003 mol) in a 3N solution of HCI in water (30ml) was stirred at 80°C for 12 hours. The solvent was evaporated. The residue was dried, yielding 0.18g of intermediate d-4. The crude product was used directly in the next reaction step.
A mixture of d-4 (0.0003 mol), 2-methyl-aniline (0.0005 mol), l-(3-dimethylamino- propyl)-3-ethylcarbodiimide hydrochloride (0.0005 mol) and 1-hydroxybenzotriazole (0.0005 mol) in CH2C12 (20ml) was stirred at room temperature for 24 hours. A 10% solution of K2CO3 in water was added. The aqueous layer was saturated with K2CO3 (powder). The organic layer was separated, dried (over MgS04), filtered and the solvent was evaporated until dryness. The residue (0.2g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH NH4OH 80/20/1; lOμm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.29g (14%). This fraction was taken up in diisopropyl ether, then CHsOH/diisopropylether. The precipitate was filtered off and dried, yielding 0.007g of 3-(3-hydroxy-6-methyl- pyri(lm-2-ylme1hyl)-2-(l-methyl-piperidm-4-ylamino)-3H-benzoiπndazole-5- carboxylic acid m-tolylamide (4%, compound 116, melting point: 172°C). Example 5 Scheme E
e-9 e-10
A mixture of e-1 (0.0524 mol) and e-2 (0.1048 mol) was stirred at 120°C in a Parr pressure vessel for 10 hours, then taken up into H20 and extracted with ethyl acetate. The separated organic layer was purified by short open column chromatography over silica gel (eluent: QEkGb/methanol 96/4). The product fractions were collected and the solvent was evaporated until dryness, yielding 7.7g of intermediate e-3 (44%).
A mixture of e-3 (0.0312 mol), c-4 (0.0343 mol) and K2CO3 (0.1092 mol) in dimethyl formamide (100ml) was stirred at 70°C for 24 hours. H2O was then added. The rc xture was extracted with CH2CI2. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue (12.2g) was purified by column chromatography over silica gel (eluent: toluene/isopropanol NHtOH
90/10/0.5; 15-40μm). Two fractions were collected and the solvent was evaporated, yielding 4g of intermediate c-5 (28%) and 5.4g of intermediate e-6 (38%).
e-5 (0.0088 mol) was added portion wise to a 48% solution of HBr in water (40rαl).
The mixture was brought slowly to 70°C, and then stirred for 12 hours. The precipitate was filtered, washed with CH3CN and dried. The residue (4.6g, 80%) was taken up in
H2O and basified with K2CO3 (powder). The precipitate was filtered, and then waushed with ethanol. The filtrate was evaporated, yielding 3g of intermediate e-7 (52%). In an analogous way, e-8 was prepared
HCHO 37% in H2O (0.0152 mol) then NaBH3CN (0.0091 mol) were added at room temperature to a rπixture of e-7 (0.0075 mol) in CH3CN (100ml). Acetic acid (3.5ml) was added slowly at room temperature. The rnixture was stirred at room temperature for 12 hours and poured into H2O. The aqueous layer was saturated with K2CO3 (powder). The mixture was extracted with ethylacetate/CH3OH. The organic layer was separated, dried (over MgS04), filtered and the solvent was evaporated until dryness, yielding 2.6g of intermediate e-9 (87%). In an analogous way, e-10 was prepared.
A mixture of e-9 (0.0065 mol) and Raney Nickel (2.6g) in CH3OH (100ml) was hydrogenated at room temperature for 1 hour under a 3 bar pressure, and then filtered over celite. Celite was washed with CH3OH. The filtrate was evaporated The residue (2.2g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/ NHUOH 85/14/1; 15-40μm). The pure fractions were collected and the solvent was evaporated, yielding 0.85g of intermediate e-11 (35%). In an analogous way, e-12 was prepared.
A rnixture of e-11 (0.000125 mol) and 3-methyl-benzoic acid (0.00025 mol) in CH2C12 (4 ml) was stirred at room temperature. 1-hydroxybenzotriazole (0.00025 mol) and l-(3-dimemylammopropyl)-3-ethylcarbodiimide hydrochloride (0.00025 mol) were added. The reaction was stirred at room temperature for 12 hours. The solution was concentrated and a 10% solution of NaHC03 in water (2 ml) and CH3OH (2 ml) were added. The mixture was stirred and refluxed for 4 hours. CH3OH was then removed under reduced pressure and the resulting solution extracted with CH2C12. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH^yCHsOH NH OH 90/10/0.5; 15-40μm). The pure fractions were collected and the solvent was evaporated, yielding 0.04g of N-[3-(3-hydroxy-6-methyl-pyridin-2-yl- memyl)-2-(l-methyl-piperiά^-4-ylammo)-3H-ben«oimidazol-5-yl]-3-methyl- benzamide (60%, compound 65). In an analogous way, N-[l-(3-hydroxy-6-methyl- pyridin-2-ylmethyl)-2-(l -methyl-piρeridin-4-ylamino)- 1 H-benzoimidazol-5-yl]-3- methyl-benzamide (0.028 g or 42% yield, compound 78) was prepared. Example 6 Scheme F
3 f-2
A mixture of f-1 (0.0005 mol), 3-methyl-benzaldehyde (0.0006 mol), BH3CN on solid support (0.0006 mol) and acetic acid (8 drops) in CH3OH (10ml) was stirred at room temperature for 24 hours. The solid support was filtered and washed with CH3OH. The filtrate was evaporated. The residue (0.53g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH OH 92/8/0.5 to 89/10/1; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.1 l ) was crystallized from CH3OH/disopropylether. The precipitate was separated and dried, yielding 0.072g of compound f-2, i.e. 6-methyl-2-[6-(3-me1hyl-bei]zylamino)-2- (l-methyl-piperidm-4-ylammo)-benzoimidazol-l-ylmethyl]-p5 idm compound 28, melting point: 240°C). Example 7 Scheme G
g-3 g-1
9-7 g-8
A mixture of g-1 (0.0079 mol), g-2 (0.0095 mol) and triethylamine (0.0118 mol) in dimethylformamide (60ml) was stirred at 80°C for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH2CI2/H2O. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (7g) was purified by column chromatography over silica gel (eluent: 90/10/0.5; 15-40μm). The pure fractions were collected and the solvent was evaporated, yielding 1.2g of intermediate g-3 (30%).
A mixture of g-3 (0.0023 mol) and MnO2 (2.4g) in CH2C12 (80ml) was stirred at room temperature for 12 hours, and then filtered over celite. Cehte was washed with H2O. The filtrate was evaporated until dryness. The residue (1.2g) was purified by column chromatography over silica gel (eluent: CH^ CHsOH/NH OH 95/5/0.1; 35-70μm). The pure fractions were collected and the solvent was evaporated, yielding 0.8g of intermediate g-4 (67%).
Diethyl benzyl phosphonate (0.0023 mol) was added to a mixture of NaH (0.0047 mol) in tetiahydrofuran (20ml) at 5°C under N flow. The mixture was stirred at 5°C for 30 minutes. A solution of g-4 (0.0007 mol) in tetrahydrofuran (10ml) was added drop wise. The mixture was stirred at 5°C for 1 hour, and then stirred at room temperature for 12 hours. H2O was added. The mixture was extracted with CH2CI2. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was crystallized from CH3θH/2-propanone. The precipitate was filtered off and dried, yielding 0.24g of intermediate g-5 (52%).
A mixture of g-5 (0.0001 mol) in a 5N solution of HCI in 2-propanol (0.5ml) and 2-propanol (5ml) was stirred at 60°C for 4 hours, and then cooled to room temperature. The precipitate was filtered, washed with 2-propanol/diisopropylether and dried, yielding 0.058g of 2-{2-[l-(2-Annno-ethyl)-piperidm-4-ylamino]-6-styryl- benzoimidazol-l-ylmethyl}-6-methyl-pyridin-3-ol hydrochloride salt (g-6; compound 143, 63%, 3.69 HCI + 3.03 H2O, melting point: > 260°C).
A mixture of g-5 (0.0002 mol) and Pd/C 10% (0.03g) in CH3OH (10ml) and tetrahydrofuran (10ml) was hydrogenated at room temperature for 4 hours under a 2 bar pressure, and then filtered over celite. Celite was washed with H2O. The filtrate was evaporated until dryness, yielding 0.14g of intermediate g-7 (100%). This product was used directly in the next reaction step.
A mixture of g-7 (0.0002 mol) in a 5N solution of HCI in 2-propanol (1.4ml) and
2-propanol (15ml) was stirred at 60°C for 4 hours, and then cooled to room temperature. The precipitate was filtered, washed with 2-propanol/diisopropylether and dried, yielding 0.138g of g-8, 2-{2-[l-(2-am o-ethyl)-piperiά n-4-ylamino]-6- phene1hyl-benzoiιrndazol-l-ylmethyl}-6-methyl-pyridin-3-ol hydrochloride salt (87%,
3.62 HCI + 2.41 H2O, compound 140, melting point: 18FC).
Example 8 Scheme H
h-5
A mixture of h-1 (0.0027 mol), ethyl-bromo acetate (0.0032 mol) and triethylamine (0.004 mol) in dimelhylformamide (40ml) was stirred at 50°C for 1 hour, poured into ice water and extracted three times with CH2CI2. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue was taken up in 2-propanone/diisopropylether. The precipitate was filtered, washed with H2O and dried, yielding lg of intermediate h-2 (82%).
Intermediate h-3 was prepared analogous to the procedure described for the preparation of g-4.
CH3C02H (0.2ml) vfø.s added at room temperature to a mixture of h-3 (0.0004 mol), 3-methyl-aniline (0.0005 mol) and NaBH3CN (0.0005 mol) in CH3CN (20ml). The mixture was stirred at room temperature for 6 hours. CH3CO2H (0.2ml) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH2Cl2/K2CO3 10%. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness, yielding 0.22g of intermediate h-4(100%). This product was used directly in the next reaction step.
LiAlH4 (0.0008 mol) was added to a mixture of h-4 (0.0004 mol) in tetiahydrofuran (20ml) at 5°C under N2 flow. The mixture was stirred at 5°C for 1 hour, then brought to room temperature and stirred for 4 hours. A minimum of H2O and then CH2C1 were added The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.22g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/1; 15-40um). The pure fractions were collected and the solvent was evaporated. The residue (O.lg, 50%) was crystallized from CH3OH/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.08g of 2-[2-[l-(2-hydroxy-ethyl)-piperidm-4-ylamino]-6-(m-tolyl- ammo-methyl)-benzoitmdazol-l-ylm (40%, compound 145, melting point: 137°C).
Example 9 Scheme I
A mixture of i-1 (0.0185 mol) in ethanol (60ml) and H2SO436N (5ml) was stirred and refluxed for 24 hours. The solvent was evaporated until dryness. The residue was taken up in CH2C12. The organic layer was washed with a 10% solution K2CO3 in water, dried (over MgSO ), filtered and the solvent was evaporated until dryness, yielding 3.2g of intermediate i-2 (89%).
Intermediate i-3 was prepared in an analogous way to the procedure described for intermediate a-2. Intermediate i-4 was prepared in an analogous way to the procedure described for intermediate a-3. Intermediate i-5 was prepared in an analogous way to the procedure described for intermediate a-5.
A mixture of i-5 (0.0048 mol), 2-c oromethyl-6-memyl-3-pyridinol (0.0058 mol) and
K2CO3 (0.0192 mol) in dimethylformamide (20ml) was stirred at room temperature for
12 hours, poured into ice water and extracted with CH2CI2. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness.
The residue (3.4g) was purified by column chromatography over silica gel (eluent: toluene/2-propanol NH OH 83/16/1; 15-35μm). Two fractions were collected and the solvent was evaporated, yielding 0.9g of intermediate i-6 (37%) and 0.78g of intermediate i-7 (32%).
Intermediate i-8 was prepared in an analogous way to the procedure described for intermediate a-9. Intermediate i-9 was prepared in an analogous way to the procedure described for intermediate a-11. Intermediate i-10 (melting point: 221°C) was prepared in an analogous way to the procedure described for intermediate h-2. Intermediate i-11 was prepared in an analogous way to the procedure described for intermediate h-3.
Intermediate i-12 (melting point: 143°C) was prepared in an analogous way to the procedure described for intermediate h-4.
2-[2-[l-(2-Hydroxy-ethyl)-piperidm-4-ylanήno]-4-methyl-6-(m-tolylamino-methyl)- benzoimidazol-l-ylmethyl]-6-methyl-pyridin-3-ol (i-13, compound 168, melting point: 123°C) was prepared in an analogous way to the procedure described for compound h-5. Example 10
J-3 j-4
J-7 Intermediate j-2 was prepared in an analogous way to the procedure described for intermediate h-3. Diethyl cyanomethyl phosphonate (0.0052 mol) was added to a mixture of NaH (0.0105 mol) in tetrahydrofuran (30ml) at 5°C under N2 flow. The mixture was stirred at 5°C for 30 minutes. A solution of j-2 (0.0017 mol) in tetrahydrofuran (20ml) was then added. The mixture was stirred at 5°C for 1 hour, and then stirred at room temperature for 12 hours. H2O was added. The mixture was extracted with CH2C12. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH NH OH 95/5/0.1; 70-200μm). The pure fractions were collected and the solvent was evaporated, yielding 0.7g of intermediate j-3 (84%). A rnixture of j-3 (0.0014 mol) and Pd/C 10% (0.25g) in CH3OH (35ml) was hydrogenated at 40°C for 6 hours under an 8 bar pressure, then cooled to room temperature and filtered over celite. The filtrate was evaporated until dryness, yielding 0.3g of intermediate j-4 (52%).
Intermediate j-5 was prepared in an analogous way to the procedure described for intermediate h-2. Intermediate j-6 (melting point: 207°C) was prepared in an analogous way to the procedure described for intermediate i-13.
A mixture of j-6 (0.0003 mol) and Raney Nickel (0.2g) in a saturated solution of NH3 in CH3OH (25ml) was hydrogenated at room temperature for 1 hour, and then filtered over celite. The filtrate was evaporated until dryness. The residue (0.22g) was purified by column chromatography over silica gel (eluent: CH^yCHsOHZNEUOH 80/20/2; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.083g, 49%) was dissolved in ethanol/2-propanone and converted into the hydrochloric acid salt. The precipitate was filtered off and dried. The residue was crystallized from diisopropylether. The precipitate was filtered off and dried, yielding 0.08g of2-{6-(3-Ammo-propyl)-2-[l-(2-hy(koxy-ethyl)-piperidm-4-ylamino]- benzoinndazol-l-yhnethyl}-6-methyl-pyridin-3-ol hydrochloride salt (36%, 3.6 HCI, compound 157, melting point: 185°C).
Example 11 Scheme K
A mixture of k-1 (0.0019 mol), 3-chloro-propylsulfonamide (0.0022 mol) and triethylamine (0.0028 mol) in dimethylformamide (50ml) was stirred at 70°C for 48 hours, poured into ice water, saturated with K2CO3 (powder) and extracted with CH2CI2. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (1.5g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/2; 15-40μm). The pure fractions were collected and the solvent was evaporated, yielding 0.336g of intermediate k-2 (36%).
A mixture of k-2 (0.0007 mol) and MnO2 (lg) in CH2C12 (30ml) was stirred at room temperature for 6 hours, and then filtered over celite. Celite was washed with H2O. The solvent of the filtrate was evaporated until dryness, yielding 0.33g of intermediate k-3 (100%). This product was used directly in the next reaction step.
CH3CO2H (0.2ml) was added at room temperature to a mixture of k-3 (0.0004 mol), 3,5-dimethyl-aniline (0.0005 mol) and NaBH3CN (0.0005 mol) in CH3CN (20ml). The mixture was stirred at room temperature for 30 minutes. CH3CO2H (0.2ml) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH2CI2. The organic layer was washed with a 10% solution of K2CO3 in water, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue (0.26g) was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH NH4OH 90/10/1; 5μm). The pure fractions were collected and the solvent was evaporated, yielding 0.09g (32%). This fraction was crystallized from CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.083g of 2 - {4- [6- [(3 ,5-Dimethyl-phenylamino)-methyl]- 1 -(3-hydroxy-6- methyl-pyridm-2-ylmethyl)-lH-ben -ethane- sulfonic acid amide (30%, compound 147, melting point: 142°C).
Example 12 Scheme L
1-5
Intermediate 1-2 (melting point: 210°C) was prepared in an analogous way to the procedure described for intermediate k-2. Intermediate 1-3 was prepared in an analogous way to the procedure described for intermediate k-3. Intermediate 1-4 was prepared in an analogous way to the procedure described for compound k-4.
A mixture of 1-4 (0.0003 mol) in a 7N solution of NH3 in CH3OH (15ml) was stirred at 80°C for 12 hours. The solvent was evaporated until dryness. The residue (0.21g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3θH NH4θH 85/14/1; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.057g, 30%) was crystallized from 2-propanone/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.05g of 2-{4-[6-[(3,5-dimethyl- phenylamino)-methyl]-l-(3-hydroxy-6-methyl-pyriάUn-2-ylme1hyl)-lH-benzointidazol- 2-ylammo]-piperidm-l-yl}-acetamide (26%, compound 148, melting point: 206°C).
Example 13 Scheme M
A mixture of m-1 (0.0002 mol) in tetiahydrofuran (30ml) was cooled to 5°C under N2 flow. LiAlB (0.0007 mol) was added. The mixture was stirred at 5°C for 1 hour, and then stirred at room temperature for 1 hour. A minimum of H2O was added. CH2C12 was added. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.16g) was purified by column chromatography over silica gel (eluent: C^CyCHsOH/NH OH 85/15/1 ; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.073g, 53%) was crystallized from 2-propanone/CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.064g of 2-{6-[(3,5-dimemyl-phenylamino)-methyl]-2- [ 1 -(2-hydroxy-emyl)-piperi(lm-4-ylammo]-benzoimidazol- 1 -ylmethyl} -6-methyl- pyridin-3-ol (m2, 46%, compound 149, melting point: 144°C).
Example 14 Scheme N
n-7
A mixture of n-1 (0.022 mol) and N-(propylammo)-piperidine (0.0207 mol) was stirred at 140°C for 1 hour, and then taken up in CH2Cl2/CH3OH. The organic layer was washed with K2C03 10%, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: GH2CyCH3OH H4OH 92/8/1; 70-2Q0μm). The pure fractions were collected and the solvent was evaporated, yielding 2.2g of intermediate n-2 (30%).
A mixture of n-2 (0.0066 mol), n-3 (0.0073 mol) and K2CO3 (0.02 mol) in dimethylformamide (25ml) was stirred at room temperature for 24 hours, poured into H2O and extracted with CH2C12. The organic layer was separated, dried (over MgSO ), filtered and the solvent was evaporated until dryness. The residue was taken up in <m3CN/diisopropylether. The precipitate was filtered, washed with H2O and dried, yielding 1.8g of the mixture of intermediates n-4 and n-5 (61%).
LiAlH (0.012 mol) was added portion wise to a mixture of n-4 (0.002 mol) and n-5 (0.002 mol) in tetrahydrofuran (60ml) at 5°C under N2 flow. The mixture was stirred at 5°C for 1 hour, then at room temperature for 12 hours. A minimum of H2O was added. A solution of CH2CI2/CH3OH (90/10) was added. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (1.65g) was purified by column chromatography over silica gel (eluent: CH2CI2
CH3OH NK OH 80/20/3; 15-40μm). Two fractions were collected and the solvent was evaporated, yielding 0.35g of fraction 1 and 0.049g of fraction 2. Fraction 1 was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.33g of intermediate n-6 (19%, melting point: 220°C). Fraction 2 was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.43g of intermediate n-7 (26%, melting point: 146°C).
A mixture of n-6 (0.0006 mol) and Mnθ2 (0.5g) in CH2C12 (30ml) was stirred at room temperature for 12 hours, and then filtered over celite. Celite was washed with H2O. The filtrate was evaporated until dryness, yielding 0.26g of intermediate n-8 (100%). The compound was used directly in the next reaction step.
CH3CO2H (0.3ml) was added to a inixture of n-8 (0.0006 mol), 3,5-dimethyl-aniline (0.0007 mol) andNaBH3CN (0.0007 mol) in CH3CN (30ml). The mixture was stirred at room temperature for 30 minutes. CH3CO2H (0.3ml) was added. The mixture was stirred at room temperature for 24 hours. The solvent was evaporated until dryness. The residue was taken up in 2-propanone/HCl 5N/ethanol. The mixture was stirred at 80°C for 12 hours. The solvent was evaporated until dryness. The mixture was extracted with CH2CI2. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.39g) was purified by column chromatography over silica gel (eluent: CH2CyGH3OH/NH4OH 90/10/0.5; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.119g, 59%) was taken up in CHsCN/diisopropylether. The precipitate was filtered off and dried, yielding 0.17g of 2-[6-[(3,5-dimethyl-phenylamino)-methyl]-2-(3-piperidin-l-yl- propylan mo)-benzoinή(lazol-l-ylmethyl]-6-me1hyl-pyridin-3-ol (n-9, 53%, compound 170, melting point: 16FC). Example 15 Scheme O
KjCOg, DMF
o-6 o-7
2-{6-[(3,5-Dimethyl-phenylam o)-methyl]-2-[3-(4-methyl-piperazin-l-yl)- propylamino]-benzoinήd^ol-l-ylmethyl}-6-methyl-pyridin-3-ol (compound 171, melting point: 150°C) and its intermediates were prepared in an analogous way to the procedures described for preparing compound n-9. Example 16 Scheme P
p-€ p-7
p-10
Intermediate p-9 (melting point: 212°C) was prepared in an analogous way to the procedure described for compound n-9.
A mixture of p-9 (0.0004 mol) in a 3N solution of HCI in water (20ml) and tetrahydrofuran (20ml) was stirred at room temperature for 6 hours, basified with K2CO3 (powder) and extracted with CH2C12. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.25g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/ NH OH 92/8/0.5; lOμm). The pure fractions were collected and the solvent was evaporated. The residue (0.17g, 92%) was crystallized from CH3CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.127g of 3-[6-[(3,5-dimethyl-phenyl- ammo)-methyl]-l-(3-hydroxy-6-memyl-pyridm-2-ylmethyl)-lH-benzoimid^ ylamino]-propane-l,2-diol (p-10, 69%, compound 172, melting point: 128°C). Example 17 Scheme Q
2-{6-[(3,5-Dimemyl-phenylammo)-methyl]-2-[2-(4-me oxy-phenyl)-ethylamino]- benzoinno^ol-l-ylmethyl}-6-me1hyl-pyridin-3-ol (compound 187, melting point: 178°C) and its intermediates were prepared in an analogous way to the procedures described for preparing compound n-9.
The following tables list compounds that were prepared according to any one of the above examples-
Table 1
Table 2a
Table 2b
Table3
Table4
Table 5
Example 18: In vitro screening for activity against Respiratory Syncytial Virus. The percent protection against cytopathology caused by viruses (antiviral activity or EC5o) achieved by tested compounds and their cytotoxicity (CC50) are both calculated from dose-response curves. The selectivity of the antiviral effect is represented by the selectivity index (SI), calculated by dividing the CC50 (cytotoxic dose for 50% of the cells) by the EC50 (antiviral activity for 50 % of the cells). The tables in the above experimental part list the category to which each of the prepared compounds belong : Compounds belonging to activity category "A" have an pEC5o (-log of EC50 when expressed in molar units) equal to or more than 7. Compounds belonging to activity category "B" have a pEC50 value between 6 and 7. Compounds belonging to activity category "C" have a pEC50 value equal to or below 6.
Automated tetrazolium-based colorirαetric assays were used for determination of EC50 and CC50 of test compounds. Flat-bottom, 96-well plastic microtiter trays were filled with 180 μl of Eagle's Basal Medium, supplemented with 5 % FCS (0% for FLU) and 20 mM Hepes buffer. Subsequently, stock solutions (7.8 x final test concentration) of compounds were added in 45 μl volumes to a series of triplicate wells so as to allow simultaneous evaluation of their effects on virus- and mock-infected cells. Five five- fold dilutions were made directly in the microtiter trays using a robot system. Untreated virus controls, and HeLa cell controls were included in each test. Approximately 100 TCID50 of Respiratory Syncytial Virus was added to two of the three rows in a volume of 50 μl. The same volume of medium was added to the third row to measure the cytotoxicity of the compounds at the same concentrations as those used to measure the antiviral activity. After two hours of incubation, a suspension (4 x 105 cells/ml) of HeLa cells was added to all wells in a volume of 50μl. The cultures were incubated at 37°C in a 5% CO2 atmosphere. Seven, days after infection the cytotoxicity and the antiviral activity was examined spectrophotometrically. To each well of the microtiter tray, 25 μl of a solution of MTT (3-(4a5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was added. The trays were further incubated at 37°C for 2 hours, after which the medium was removed from each cup. Solubilization of the formazan crystals was achieved by adding 100 μl 2-propanol. Complete dissolution of the formazan crystals were obtained after the trays have been placed on a plate shaker for 10 min. Finally, the absorbances were read in an eight-channel computer-controlled photometer (Multiskan MCC, Flow Laboratories) at two wavelengths (540 and 690 nm). The absorbance measured at 690 nm was automatically subtracted from the absorbance at 540 nm, so as to eliminate the effects of non-specific absorption.

Claims

Claims
1. A compound having the formula
a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein
Q is Ar2, R6a, pyrrolidinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6;
G is a direct bond or Ci-ioalkanediyl optionally substituted with one or more substituents individually selected from the group consisting of hydroxy, Ci-galkyl- oxy, Ci-ealkylthio, HO(-CH2-CH2-O)„-, and Ar Ci-6alkyloxy(-CH2-CH2-O)n-;
R1 is Ar1 or a monocycUc or bicyclic heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydro- furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, quinolinyl, quinoxalinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthiridinyl, lH-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[l,2-a]- pyridinyl, 2,3-dihydro-l,4-dioxino[2,3-b]pyridyl or a radical of formula
wherein each of said monocyclic or bicyclic heterocycles may optionally be substituted with 1 or where possible more, such as 2, 3, 4 or 5, substituents individually selected from the group of substituents consisting of halo, hydroxy, amino, cyano, carboxyl, Ci-ealkyloxy, Ci-eal yloxyCi-ealkyl, Ar1, hydroxyCi-ealkyl, mono- Ci-6alkyl-S02-NR4a-, Ar^SOa-NR48-, C1-6alkyloxycarbonyl, -C(=O)-NR4aR4b, HO(-GH2-CH2-0)„-, halo(-CH2-CH2-O)„-, Cι-6alkyloxy(-CH2-CH2-O)„-, Ar1C1-6alkyloxy(-CH2-CH2-0)n- and mono-and di(C1-6alkyl)amino(-CH2-CH2-O)n-; one of R2a and R2b is cyanoCi-βalkyl, cyanoC2-6alkenyl, Ar3C1-6alkyl, (Ar3)(OH)Cι-6alkyl, Het-Ci-ealkyl, NCR^R^C^alkyl, Ar3C2-6alkenyl, Het-C2-6alkenyl, Ar3aminoCι-6alkyl, Het-aminoCi-ealkyl, Het-Ci-βalk lamino- Cι.6alkyl, Ar3thioCι-6alkyl, Het-thioCi-βalkyl, Ar3sulfonylCι-6alkyl, Het-sulfonyl- Ci-βalkyl, Ar3aminocarbonyl, Het-arninocarbonyl, Ar3(CH2)„aminocarbonyl, Het-(CH2)naminocarbonyl, Ar3carbonylamino, Het-carbonylamino, Ar3(CH2)ncarbonylamino, Het-(CH2)ncarbonylarnino, Ar3(CH2)namino; and the other one of R2" and R2 is hydrogen; in case R2a is hydrogen, then R3 is hydrogen; in case R is hydrogen, then R3 is hydrogen or R4a and R4b can be the same or can be different relative to one another, and are each independently hydrogen or Ci-βalkyl; or R4a and 4b taken together may form a bivalent radical of formula -(CH )S- wherein s is 4 or 5; R5 is hydrogen or R6 is hydrogen or optionally substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR7aR7b, C3-7cycloalkyl, Ar2, hydroxy, Ai -oxy-, carbonyl, Ar2(CH2)ncarbonyl, amino- carbonyloxy, C1- alkylcarbonyloxy, Ar2carbonyloxy, Ar^CH^ncarbonyloxy, Cι_4alkoxycarbonyl(CH2)nθxy, mono- or mono- or sulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or Cι_6alkyl; R6a is substituted with one or more substituents each independently selected from the group consisting of trifluoromethyl, NR7aR7b, C3_7cycloalkyl, Ar2, hydroxy, Ar2(GH2)noxy, Ar (CH2)nthio, hydroxycarbonyl, aminocarbonyl, oxy, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, Cι^alkoxycarbonyl(CH2)noxy, mono- or mono- or di(Cι-4alkyl)aminocarbonyloxy, aminosulfonyl, mono- or di(Cι^alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with oxo or Chalky!;
R7a is hydrogen, C^aUcyl, formyl or Cι-6alkylcarbonyl; R is hydrogen, Ci-βalkyl, formyl or Ci-βalkylcarbonyl; R8a is Ar3, Ci-βalkyl, hydroxyCi-ealkyl, cyanoCι-6alkyl, aminoCι-6alkyl, mono-or ώ(Cι-6alkyl)aminoCι^alkyl, Ar3C1^alkyl, Het-C1-6alkyl, aminocarbonyl-Cι-6-aIkyl, carboxyl-Cι-6-alkyl;
R8 is Ar3, C1-6alkyl, Ci-ealkoxyCi-βalkyl, cyanoCt-ealkyl, aminoCi-ealkyl, mono-or Ar3Cι-6alkyl, each n independently is 1, 2, 3 or 4; each m independently is 1 or 2; each p independently is 1 or 2;
Ar1 is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from halo, hydroxy, Chalky! hydroxyCι.6alkyl, polyhaloC1-6alkyl, and Cι-6alkyloxy; Ar2 is phenyl or phenyl substituted with 1 or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, amino, cyano, Ci-βalkyl, Ci-βalkyloxy, aminosulfonyl, aminocarbonyl, hydroxycarbonyl, C alkylcarbonyl, mono- or (h(Cι-4alkyl)amino, mono- or (h(C1- alkyl)aminocarbonyl, mono- or di(C1- alkyl)ammosulfonyl, mono- or and C1- alkoxycarbonyl;
Ar3 is phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl, wherein said phenyl, naphtyl, 1,2,3,4-tetrahydro-naphthalenyl or indanyl may optionally and each individually be substituted with one or more, such as 2, 3 or 4, substituents selected from the group consisting of halo, hydroxy, mercapto, amino, cyano, C^alkyl, C2-6alkenyl, C2-6alkynyl, Ar1, hydroxyC1-6alkyl, polyhaloCi-βalkyl, aminoCi-δalkyl, cyanoC1-6alkyl, aminocarbonyl, AXOXV, Ar -thio, Ar1 -amino, aminosulfonyl, arninocarbonyl-Ci-ealkyl, hydroxycarbonyl-d-ealkyl, hydroxycarbonyl, C1-4alkylcarbonyl, mono- or mono- or di(C1- alk l)aπ inocarbonyl, mono- or C1-4alkylcarbonylamino and Ci^alkoxycarbonyl; Het is a heterocycle being selected from tetøhydrofuranyl, tetrahydrothienyl, dioxanyl, dioxolanyl, pyrrolidinyl, pyrrolidinonyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl, each of said heterocycle may optionally be substituted with oxo, amino, Ar1, C1-4alkyl, hydroxyCi-ealkyl, Ar1Cι- alkyl, mono- or mono- or di^^alky^amino, or with two C1- alkyl radicals.
2. A compound according to claim 1 wherein the compound has the formula (I-a-1):
wherein Q, R5, G and R1 are as claimed in claim 1 ; and Alk is Ci-ealkanediyl; R8chas the same meanings of R8a, as claimed in claim 1, and also may be hydrogen; R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as claimed in claim 1.
3. A compound according to claim 1 wherein the compound has the formula (I-b-1):
wherein Q, R5, G and R1 are as claimed in claim 1 ; and Alk is Ci-galkanediyl; R8chas the same meanings of R8a, as claimed in claim 1, and also may be hydrogen; R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as claimed in claim 1.
4. A compound according to claim 1 wherein the compound has the formula (I-c):
wherein t, G, R1, R23, R2b, R3, R5 and R6 are as claimed in claim 1.
A compound according to claim 1 wherein the compound has the formula (I-d-2):
wherein t, R5, R6, G and R1 are as claimed in claim 1 ; and Alk is Ci-ealkanediyl; R8chas the same meanings of R8a, as claimed in claim 1, and also may be hydrogen; R9, R10, R11 independently from one another have the same meanings as the substituents on Ar3 as claimed in claim 1.
6. A compound according to claim 1 wherein the compound has the formula (I-e-2):
wherein t, R5, R6, G and R1 are as claimed in claim 1 ; and R8chas the same meanings of R8a, as claimed in claim 1, and also may be hydrogen; R9, R10, Rn independently from one another have the same meanings as the substituents on Ar3 as claimed in claim 1.
7. A compound according to any of claims 4 to 6 wherein t is 2.
8. A compound according to any of claims 1 - 7, wherein G is CXoalkanediyl.
9. A compound according to in any of claims 1 - 7, wherein G is methylene.
10. A compound according to any of claims 1 - 9, wherein R1 is pyridyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, carboxyl, C1-6alkyloxy, Ci-ealkylthio, Ci-galkyloxyCi-βalkyl, Ar1, Ar1C1-6alkyl, Ar1Cι_6alkyloxy, mono-or mono-or d (Cι-6alkyl)amino- Ci-βalkyl, Ci-βalkylcarbonylarnino, Ci_6alkyl-SO2-NR4a-, AXsOa-NR43-, Ci-ealkyloxycarbonyl, -C(=O)-NR4aR4 , HO(-CH2-CH2-O)n-, halo(-CH2-CH2-O)n-, C1-6alkyloxy(-CH2-CH2-0)n-, (-CH -CH2-O)n- and mono-or (C1-6alkyl)amino(-CH2-CH2-O)n-.
11. A compound according to any of claims 1 - 9, wherein R1 is pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy and Chalky!.
12. A compound according to any of claims 1 - 9, whereϋfR1 is -Ar1, quinolinyl, benzimidazolyl, a radical of formula
or pyrazinyl; wherein each of the radicals Ar1, quinolinyl, benzimidazolyl, (c-4), or pyrazinyl may optionally be substituted with the substitutents of said radicals as claimed in claiml.
13. A compound according to any of claims 1 - 9, wherein R1 is phenyl optionally substituted with one, two or three radicals selected from the group consisting of halo, hydroxy, quinolinyl; a radical (c-4) wherein m is 2, optionally substituted with up to two radicals selected from Ci-βalkyl; benzimidazolyl optionally substituted with Chalky!; pyrazinyl optionally substituted with up to three radicals selected from Chalky!.
14. A compound according to any of claims 1 - 13, wherein one of R23 andR3a is selected from cyanoCi-βalkyl, cyanoC2-6alkenyl, Ar3C1-6alkyl, (Ar3)(OH)Cι-6alkyl, Het-Ci-ealkyl, N(R8aR8b)Cι^alkyl, Ar3C2-6alkenyl, Het- C^alkenyl, Ar3aminoCι^alkyl, Het-aminoC^alkyl, Het- -δalkylaminoCi-ealkyl, Ar3thioC1-6alkyl, Het-thioC^alkyl, Ar3sulfonylC1-6alkyl, Het-sulfonylCι-6alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)narninocarbonyl, Het- (CH2)naminocarbonyl, Ar3carbonylamino, Ar3(CH2)namino; and the other one of R28 and R2b is hydrogen.
15. A compound according to any of claims 1 - 13, wherein one of R23 and R3a is selected from N(R8aR8b)Cι-6alkyl, Ar3C2-6alkenyl, Het-aminoCi-ealkyl, Het-Ci-ealkylamino- C1-6alkyl, Ar3thioC1^alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl; and the other one of R2a and R2 is hydrogen.
16. A compound according to any of claims 1 - 13, wherein one of R22 andR3a is selected from N(R8aR8b)C1-6alkyl, Ar3aminoCι^alkyl; and the other one of R2a and R2 is hydrogen.
17. A compound according to any of claims 14 - 16, wherein in case R >2a is hydrogen then R is hydrogen; in case R ,2b is hydrogen then R is hydrogen or Ci-ealkyl.
18. A compound according to any of claims 1 - 17, wherein R5 is hydrogen.
19. A compound according to any of claims 1 - 18, wherein Q is R6a, wherein R63 is Ci-βalkyl substituted with one or with two substituents each independently selected from the group consisting of trifluoromethyl, NR^R715, Ar2, hydroxy, C1- alkoxy, Ar2(CH2)noxy, hydroxycarbonyl, aminocarbonyl, oxy, mono- or aminosxilfonyl, mono- or or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, pφeridinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and Ci-βalkyl;
20. A compound according to any of claims 1 - 18, wherein Q is R6a, wherein R68 is C1-6alkyl substituted with Ar2 or hydroxy, or C^alkyl substituted with two hydroxy radicals, or C^alkyl substituted with diCi-δalkyl-dioxolanyl, pyrrolidinyl, piperidinyl, piperazinyl,
21. A compound according to any of claims 1 - 18, wherein Q is pyrrohdinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6; wherein R6 is hydrogen or Ci-ealkyl optionally substituted with one or with two substituents, each independently selected from the group consisting of trifluoromethyl, NR7aR7b, Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, mono- or di(Cι^alkyl)arninocarbonyl, arninosulfonyl, mono- or d^Ci^alkyl)- aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl and pyridyl, wherein each of said heterocycle may optionally be substituted with with one or two radicals selected from oxo and C1-6alkyl.
22. A compound according to any of claims 1 - 18, wherein Q is pyrrohdinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6; wherein R6 is hydrogen or Chalky! optionally substituted with NR^R713, Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or Ci-βalkyl substituted with two hydroxy radicals, or C^aUcyl substituted with a heterocycle selected from dioxolanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, wherein each of said heterocycle may optionally be substituted with oxo or with one or two C1-6alkyl radicals.
23. A compound according to any of claims 1 - 18, wherein Q is pyrrohdinyl substituted with R6, piperidinyl substituted with R6 or homopiperidinyl substituted with R6; wherein R6 is hydrogen or substituted with Ar2 or Ci-ealkyl substituted with piperidinyl or with piperazinyl.
24. A compound according to any of claims 21 - 23, wherein Q is piperidinyl substituted with R6.
25. A compound according to any of claims 1 - 24, wherein R8a is Ar3, Ci-βalkyl, hydroxyCi-ealkyl, mono-or Ar3Cι_6alkyl, Het-Ci-βalkyl, arrαinocarbonyl- C^alky-, carboxyl-Ci-6-alkyl; and R8b is Ar3.
26. A compound according to any of claims 1 - 24, wherein R8a is C^aUyl, hydroxyCi-ealkyl, Ar3Cι^alkyl, Het-C^alkyl, aminocarbonyl- C^-alkyl; andR8b is C^alkyl, hydroxyCi-δalkyl, Ar3Cι^aIkyl, Het-Cι-6alkyl.
27. A compound according to any of claims 1 - 26, wherein Ar3 is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, mercapto, amino, cyano, Ci-ealkyl, C -6alkenyl, C2-6 lkynyl, Ar1, hydroxy- , aminoCi-βalkyl, cyanoCi-ealkyl, aminocarbonyl, Q-ealkyloxy, AXoxy, AXthio, Ar1 -amino, aminosulfonyl, aminocarbonyl- Ci-ealkyl, hydroxycarbonyl,
28. A compound according to any of claims 1 - 27, wherein Ar3 is phenyl substituted with one, two or three substituents selected from halo, C^ Ucyl or hydroxyCi-βalkyl.
29. A compound as claimed in any one of claims 1 to 28 for use as a medicine.
30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 23.
31. A process for preparing a pharmaceutical composition as claimed in claim 25, said process comprising intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound as claimed in any one of claims 1 to 23.
32. The use of a compound as claimed in any of claims 1 to 23 for the manufacture of a medicament for inhibiting RSN replication.
33. A process for preparing a compound as claimed in any of claims 1 to 23, said process comprising (a) reacting an intermediate of formula (TT) with a reagent (ITT) as in the following reaction scheme: (b) reacting an intermediate of formula (TV) with a reagent (V) thus obtaining a compound of formula (I-c-1) as in the following reaction scheme:
(c) reducing an intermediate (VH-a) or (VH-b) to obtain an intermediate (VHI-a) or (VTH-b) and subsequently oxidizing the alcohol group in (VTlI-a) or (Vffl-b) with a mild oxidant to obtain an intermediate (D -a) or (TX-b) and subsequently alkylating (K-a) or (EX-b) to obtain (I-f-1) or (I-f-2), which is further alkylated to obtain (I-g-1) or (I-g-2) as in the following reaction schemes:
reduction
oxidation
(Vll-b) (Vlll-b) oxidation
(IX-b ) alkylation arylation
(i-g-2)
(d) converting the alcohol group in (Vlll-a) or (Vlll-b) to a leaving group and subsequently reacting the thus obtained products with an amine thus obtaining (I-g-1) or (I-g-2)
(i-g-1) (e) converting an intermediate (IX-a) or (EX-b) to a compound (I-g-1) or (I-g-2) using a Wittig or Wittig-Horner procedure; selectively reducing the double bond in (I-g-1) or (I-g-2) thus obtaining compounds (I-i-1) or (I-i-2); reducing the cyano group in (I-i-1) or (I-i-2) to a methyleneamine group thus obtaining (T-j-1) or (I -j-2); mono- or dialkylating the latter thus obtaining compounds (I-k-1) or (I-k-2); (1-1-1) or (1-1-2):
alkylation arylation
alkylation arylation (I-1-1 )
(IX-b) (I-g-2)
(l-h-2) (I-i-2)
reduction (l-j-2)
alkylation arylation
(l-k-2) (1-1-2) and optionally converting the thus obtained compounds of formula (I) into their pharmaceutically acceptable base-addition or acid addition salt form by treatment with a suitable base or acid and conversely treating the base-addition or acid addition salt form with an acid or a base to obtain the free form of the compound of formula (I).
34. A compound of formula (VH-a), (VH-b), (VHI-a), (Vm-b), (TX-a), (EX-b), (I-f-1), (I-f-2), (I-g-1) or (I-g-2) said formula being as in claim 33, wherein G, R1, R2*, R2 , R3, R5, R8a, R815, R12 are as claimed in claim 1, and wherein Q is pyrrolidinyl, piperidinyl or homopiperidinyl, substituted on their nitrogen with a radical R6 which is C^aUcyl optionally substituted with one or two, substituents each independently selected from the group consisting of trifluoromethyl, C3-7cycloalkyl, Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, Ar2(CH2)nCarbonyl, aminocarbonyloxy, Cι-4alkylcarbonyloxy, Ar2(CH2)ncarbonyloxy, . C1- aIkoxycarbonyl(CH2)noxy, mono- or mono- or sulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, triazolyl, piperidinyl, homopiperidinyl, piperazinyl, dioxolanyl, dioxanyl, pyridyl and tetrahydropyridyl, wherein each of said heterocycle may optionally be substituted with one or two substituents selected from oxo or C^alkyl; and wherein said R6 can be represented by R615, as well as the pharmaceutically acceptable salt forms thereof, and the possible stereoisomeric forms thereof.
35. A compound according to claim 34 wherein R61" is Chalky! optionally substituted with Ar2, hydroxy, aminocarbonyl, aminosulfonyl, or Ci-βalkyl substituted with two hydroxy radicals, or Chalk ! substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-Cι-6alkyl-piperazinyl.
36. A compound according to claim 34 wherein R66 is Chalky!.
37. A compound formula (VH-a), (VH-b), (VHI-a), (VHI-b), (EX-a), (EX-b), (I-f-1), (I-f-2), (I-g-1) or (I-g-2) said formula being as in claim 33, wherein G, R1, R2a, R2b, R3, R5, R8a, R8 and R12 are as claimed in claim 1 and wherein Q is R^ wherein R613 is as claimed in claim 1.
38. A compound according to claim 37 wherein R^ is Chalky! optionally substituted with Ar2, hydroxy, aminocarbonyl, aminosulfonyl, or Chalky! substituted with two hydroxy radicals, or Chalk ! substituted with pyrrolidinyl, piperidinyl, piperazinyl, 4-Ci-6alkyl-piperazinyl.
39. A compound according to claim 37 wherein R615 is Chalky!.
EP04804954A 2003-12-18 2004-12-20 5- or 6-substituted benzimidazole derivatives as inhibitors of respiratory syncytial virus replication Active EP1697347B1 (en)

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WO2005058874A1 (en) 2005-06-30
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